Benzazole derivatives, compositions, and methods of use as aurora kinase inhibitors

ABSTRACT

The present invention relates to compounds and methods from the treatment of cancer. The invention provides compounds that inhibit Aurora kinase, pharmaceutical compositions comprising compounds that inhibit Aurora kinase, and methods for the treatment of cancer using the compounds of the presentation invention or pharmaceutical compositions comprising compounds of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. § 119(e)of U.S. Provisional Application No. 60/772,497, filed Feb. 10, 2006,entitled “Benzazole Derivatives, Compositions, and Methods of Use asAurora Kinase Inhibitors”, and U.S. Provisional Application No.60/791,187, filed Apr. 11, 2006, entitled “Benzazole Derivatives,Compositions, and Methods of Use as Aurora Kinase Inhibitors”, thedisclosures of which are herein incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to azole derivatives useful as inhibitorsof Aurora kinase, and methods of use of the benzazole derivatives totreat cancer.

BACKGROUND OF THE INVENTION

A better understanding of the signal transduction pathways and enzymesunderlying disease etiology and pathophysiology has greatly facilitatedthe search for new therapeutic agents. One important class of enzymesthat has been the subject of intensive investigation for targetingdisease processes is protein kinases.

Protein kinases are key regulators of cell growth, differentiation,metabolism and function. Protein kinases are a family of structurallyrelated enzymes that are responsible for control of a variety of signaltransduction processes within the cell (The Protein Kinase Facts Book, Iand II, Academic Press, San Diego, Calif.: 1995). Almost all proteinkinases contain a catalytic domain consisting of approximately 250 to300 amino acids. In general, protein kinases mediate their intracellularsignaling by catalytic transfer of a γ-phosphoryl group from ATP totarget protein substrates. Protein kinases are classified into familiesby the substrates they phosphorylate. Sequence motifs have beenidentified that correspond to each of these kinase families such asprotein-tyrosine, protein-serine/threonine, and lipids (Hanks, S. K.,Hunter, T., FASEB J. 1995, 9 576-596; Knighton et al., Science 1991,253, 407-414; Hiles et al., Cell 1992, 70, 419-429). In response to avariety of stimuli, protein kinases allow the cell to make decisions byacting as a molecular “on/off” switch that can either perturb orregulate target protein function.

Abnormal protein kinase-mediated signal transduction in a cell is theunderlying cause of many pathophysiological states. These disease statesinclude, but are not limited to, autoimmune disease, allergy and asthmadiseases, neurological and neurodegenerative diseases, metabolicdiseases, Alzheimer's disease, cardiovascular disease, and cancer.Accordingly, protein kinases are considered rational drug targets fortherapeutic intervention and protein kinase inhibitors are thought to beeffective therapeutic agents.

The aurora family of serine/threonine protein kinases is essential forcell proliferation (Trends in Cell Biology 9, 454-459 (1999); Nat. Rev.Mol. Cell. Biol. 2, 21-32 (2001); Trends in Cell Biology 11, 49-54(2001)). The human aurora kinase family consists of three highlyhomologous kinases (A or “2”, B or “1” and C or “3”). During normal cellproliferation, these proteins are involved in chromosome segregation,mitotic spindle function, and cytokinesis. Aurora kinase expression islow in resting cells and peaks during the G2 and mitosis phases of thecell cycle. Several proposed mammalian substrates for Aurora kinasesthat are important for cell division include histone H3, TPX2, myosin IIregulatory light chain, CENP-A, and protein phosphatase 1.

Since the elucidation of their key role in mitotic progression and celldivision, Aurora kinases have been closely linked to tumorigenesis. Forexample, Aurora kinase gene amplification and overexpression has beenreported in many cancers. A coding single nucleotide polymorphism (SNP)has been identified that is significantly more frequent in advancedgastric cancer relative to early stage gastric cancer, and this SNPcorrelates with elevated kinase activity (Cancer Lett. Jan. 10, 2006).Overexpression of Aurora A induces centrosome amplification, aneuploidyand transformation in rodent fibroblasts (Bischoff, J. R. et al. EMBO. J17, 3052-3065 (1998); Nat. Genet. October 20 (2):189-93 (1998)). Thisoncogenic activity is likely due to the generation of chromosomeinstability. Indeed, there is a strong correlation between Aurora Aoverexpression and chromosome aneuploidy in breast and gastric cancer.(Int., J. Cancer 92, 370-373 (2001); British Journal of Cancer 84,824-831 (2001)). Aurora B expression is elevated in cell lines derivedfrom tumors of the colon, breast, lung, melanoma, kidney, ovary,pancreas, CNS, gastric tract and leukemias (Oncol Res. 2005;15(1):49-57; Tatsuka et al. 1998, 58, 4811-4816; British Journal ofCancer 84, 824-831 (2001); EMBO J. 17, 3052-3065 (1998)). In prostatecancer, increased nuclear expression of Aurora B was observed in highGleason grade anaplastic prostate cancer tissues relative to low andintermediate grades, and Aurora B expression was accompanied by thephosphorylation of the histone H3 substrate (Prostate 66(3): 326-33(2003)). Aurora C is overexpressed in primary colorectal cancer (Journalof Biological Chemistry 274, 7334-7340 (1999); Jpn. J. Cancer Res. 91,1007-1014 (2000)).

Because Aurora kinase inhibition in tumor cells can result in mitoticarrest and apoptosis, these kinases are important targets for cancertherapy. Given the central role of mitosis in the progression ofvirtually all malignancies, inhibitors of the Aurora kinases thereforeare expected to have the potential to block growth of cancers or tumorsand have application across a broad range of human cancers or tumors.

SUMMARY OF THE INVENTION

This invention provides substituted benzazole derivatives andcompositions that inhibit Aurora kinase. In an embodiment, the presentinvention provides compounds of Formula (I) as depicted below. Inanother embodiment, the present invention provides methods ofpreparation of compounds of Formula (I). In another embodiment, thepresent invention provides pharmaceutical compositions comprising thecompounds of Formula (I). In another embodiment, the present inventionprovides methods of using the compounds of Formula (I) andpharmaceutical compositions comprising a compound of Formula (I) intreating human or animal disorders. The compounds of the invention areuseful as inhibitors of Aurora kinase and thus may be useful for themanagement, treatment, control and adjunct treatment of diseasesmediated by Aurora kinase activity such as cell proliferative disorders,including cancer.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows MiaPaCa-2 tumor growth curves, where ▴ represents vehiclefor Example 88 and erlotinib; ◯ represents erlotinib at a dose of 50mg/kg, p.o., daily for 14 days; □ represents Example 88 at a dose of 10mg/kg, i.p., b.i.d. daily for 10 days; and ● represents Example 88 anderlotinib.

FIG. 2 shows MiaPaCa-2 tumor growth curves, where ▪ represents vehiclefor Example 88 and gemcitabine; ▴ represents Example 88 at a dose of 10mg/kg, i.p., b.i.d. daily for 10 days; □ represents gemcitabine at asdose of 120 mg/kg, i.p., q3d×4; and ◯ represents Example 88 andgemcitabine.

FIG. 3 shows BT-474 tumor growth curves in athymic SCID mice, where ▪represents vehicle for Example 88; ◯ represents trastuzumab at a dose of10 mg/kg, i.p., twice weekly, for 4 weeks; ▴ represents Example 88 at adose of 30 mg/kg, i.p., b.i.d. daily for 3 days, then 2 days off, for atotal of 5 cycles; and □ represents Example 89 and trastuzumab.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds that inhibit Aurora kinase.These compounds are useful for inhibiting Aurora kinase in vitro, andmay be useful for the treatment of cell proliferative disorders,including cancer in a patient.

In one aspect, the present invention provides a compound of Formula (I):

wherein

-   X is —NH—, —O—, or —S—,-   E is —CH₂—, —NH—, —O—, or —S—,-   G¹ and G² are independently selected from the group consisting of:    aryl, heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fused    cycloalkylheteroaryl, fused heterocyclylaryl, and fused    heterocyclylheteroaryl group, wherein G¹ and G² are optionally    substituted 1 to 7 times with substituents independently selected    from the group consisting of R^(b);-   L¹ is selected from the group consisting of: a direct bond, —CH₂—,    —O—, —O—CH₂—, —CH₂—O—, —N(R⁶)—, —C(O)—, —C(O)N(R⁶)—, —N(R⁶)C(O)—,    —N(R⁶)C(O)N(R⁷)—, —N(R⁶)C(O)O—, —OC(O)N(R⁶)—, —N(R⁶)SO₂—,    —SO₂N(R⁶)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)₂—,    —N(R⁶)SO₂N(R⁷)—, —N═N—, —C(R⁸)═C(R⁹)—, and —C≡C—,    -   wherein        -   R⁶ and R⁷ are independently selected from the group            consisting of R^(d) and R^(e); and        -   R⁸ and R⁹ are independently selected from the group            consisting of R^(e) and R^(f);-   A is a direct bond or the group -L²-Y-L³-, wherein    -   L² and L³ are independently selected from the group consisting        of:        -   a direct bond,        -   —C₁₋₁₀ alkylene,        -   —C₂₋₁₀ alkenylene,        -   —C₂₋₁₀ alkynylene,        -   -arylene,        -   -heteroarylene,        -   -cycloalkylene, and        -   -heterocyclylene,        -   wherein the carbon atoms of the alkylene, alkenylene,            alkynylene, arylene, heteroarylene, cycloalkylene, and            heterocyclylene groups are optionally substituted 1-4 times            with a substituent independently selected from R^(c);    -   Y is a direct bond, —O—, —N(R¹⁰), —S—, SO₂—, —C(O)N(R¹⁰)—,        —N(R¹⁰)—C(O)—, —N(R¹¹)C(O)N(R¹⁰)—, —N(R¹⁰)SO₂—, —SO₂N(R¹⁰)—,        —C(O)—O—, —N(R¹¹)SO₂N(R¹⁰)—, —O—CO—, or —N═N—,        -   wherein            -   R¹⁰ and R¹¹ are independently selected from the group                consisting of: R^(d) and R^(e), and-   Q is selected from the group consisting of-   1)    -   wherein R¹⁶ and R¹⁷ are independently selected from the group        consisting of: R^(d) and R^(e);-   2) -heteroaryl;    -   -heterocyclyl;    -   -fused cycloalkylheteroaryl;    -   -fused heterocyclylaryl;    -   -fused heterocyclylheteroaryl;    -   -fused arylheterocyclyl;    -   -fused heteroarylcycloalkyl; and    -   -fused heteroarylheterocyclyl;    -   wherein the heteroaryl, heterocyclyl, fused        cycloalkylheteroaryl, fused heterocyclylaryl, fused        heterocyclylheteroaryl, fused arylheterocyclyl, fused        heteroarylcycloalkyl, and fused heteroarylheterocyclyl groups        are optionally substituted 1-4 times with a substituent        independently selected from R^(c); and-   3) a ring system comprising at least one nitrogen atom selected from    the group consisting of:    wherein    -   n, m, p, q and r are independently 0-4 such that n+m+p equals        from 2-5 and q+r equals from 2-5, and the cycloalkyl or        heterocyclo ring system is optionally substituted on the (CH₂)        carbon atoms 1-2 with R¹⁸ or R¹⁹, wherein R¹⁸ and R¹⁹ are        independently selected from the group consisting of R^(f) and        R^(g),    -   J¹ is selected from the group consisting of:    -   J³ and J⁵ are independently selected from the group consisting        of —CH₂—, —O—, —S—, —S(O)₂—, —C(O)—, —C(O)N(H)—, —NHC(O)—,        —NHC(O)N(H)—, —NHSO₂—, —SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,    -   R²⁹ and R³⁰ are independently selected from the group consisting        of R^(d) and R^(e);    -   R³¹ is R^(f);-   R¹ is R^(b);-   R^(b) is    -   a) -cycloalkyl,    -   b) -cyano,    -   c) —OR^(d),    -   d) —NO₂,    -   e) -halogen,    -   f) -haloalkyl,    -   g) —S(O)_(s)R^(d),    -   h) —SR^(d),    -   i) —S(O)₂OR^(d),    -   j) —S(O)_(s)NR^(d)R^(e),    -   k) —NR^(d)R^(e),    -   l) —O(CR^(f)R^(g))_(t)NR^(d)R^(e),    -   m) —C(O)R^(d),    -   n) —CO₂R^(d),    -   o) —CO₂(CR^(f)R^(g))_(t)C(O)NR^(d)R^(e),    -   p) —OC(O)R^(d),    -   q) —C(O)NR^(d)R^(e),    -   r) —NR^(d)C(O)R^(e),    -   s) —OC(O)NR^(d)R^(e),    -   t) —NR^(d)C(O)OR^(e),    -   u) —NR^(d)C(O)NR^(d)R^(e),    -   v) —CF₃,    -   w) —OCF₃    -   x) —C₁₋₁₀ alkyl,    -   y) —C₂₋₁₀ alkenyl,    -   z) —C₂₋₁₀ alkynyl,    -   aa) —C₁₋₁₀ alkylene-aryl,    -   bb) —C₁₋₁₀ alkylene-heteroaryl, or    -   cc) -heteroaryl,    -   wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, and        cycloalkyl groups are optionally substituted 1-4 times with a        substituent independently selected from R^(c);-   R^(c) is    -   a) -halogen,    -   b) -amino,    -   c) -carboxy,    -   d) —C₁₋₄ alkyl,    -   e) —O—C₁₋₄ alkyl,    -   f) -cycloalkyl,    -   g) —O-cycloalkyl,    -   h) -aryl,    -   i) —C₁₋₄ alkylene-aryl,    -   j) -hydroxy,    -   k) —CF₃,    -   l) —O-aryl,    -   m) -heteroaryl,    -   n) -heteroaryl-C₁₋₁₀ alkyl,    -   o) heterocyclyl,    -   p) —CO₂—C₁₋₁₀ alkyl, or    -   q) —CO₂—C₁₋₁₀ alkyl-aryl,-   R^(d) and R^(e) are independently selected from hydrogen, C₁₋₁₀    alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, cycloalkyl, —C₁₋₁₀    alkylene-cycloalkyl, aryl, heterocyclyl, wherein alkyl, alkenyl,    alkynyl, cycloalkyl, aryl, heterocyclyl groups are optionally    substituted with one to four substituents independently selected    from R^(c); or R^(d) and R^(e) together with the atoms to which they    are attached form a heterocyclic ring of 5 to 7 members containing    0-2 additional heteroatoms independently selected from oxygen,    sulfur and nitrogen and optionally substituted with 1-3 times with    R^(c),-   R^(f) and R^(g) are independently selected from hydrogen, C₁₋₁₀    alkyl, cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl, and aryl, wherein    alkyl, cycloalkyl, and aryl groups are optionally substituted with    one to four substituents independently selected from R^(c); or R^(f)    and R^(g) together with the carbon to which they are attached form a    ring of 5 to 7 members containing 0-2 heteroatoms independently    selected from oxygen, sulfur and nitrogen optionally substituted    with 1-3 times with R^(c),-   S is an integer from 1 to 2,-   t is an integer from 1 to 10,-   u is an integer from 0 to 1,-   v is an integer from 0 to 2,    or a pharmaceutically acceptable salt or prodrug thereof.-   In an embodiment, X is —NH—.-   In another embodiment, X is —NH— and E is —NH—.-   In an embodiment of the compound of Formula (I), G² is selected from    the group consisting of: phenyl, naphthyl, isoquinolin-3-yl,    pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl,    thiazole-2-yl, imidazole-2-yl, benzothiazole-2-yl, and    4,5,6,7-tetrahydro-thiazolo[5,4-c]-pyridine-2-yl,    -   wherein G² is optionally substituted 1-4 times with a        substituent selected from the group consisting of R^(b).-   In a further embodiment, G² is substituted with at least one    substituent selected from the group consisting of: halo, phenyl,    C₁₋₁₀ alkyl, piperazine-1-yl, 4-(C₁₋₁₀ alkyl)-piperazine-1-yl, C₁₋₁₀    alkoxy, haloalkyl, cycloalkyl, and C₁₋₁₀ alkylene-cycloalkyl.-   In a further embodiment, G² is phenyl, naphthyl, isoquinolin-3-yl,    pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl,    thiazole-2-yl, imidazole-2-yl, benzothiazole-2-yl, wherein G is    unsubstituted or substituted with at least one substituent selected    from the group consisting of: chloro, fluoro, methyl, ethyl, propyl,    isopropyl, tert-butyl, butyl, phenyl, methoxy, trifluoromethyl,    trifluoromethoxy, and cyclopentyl.-   In an embodiment of the compound of Formula (I), L¹ is —C(O)—NH— or    —NH—C(O)—.-   In another embodiment of the compound of Formula (I), L¹ is    —C(R⁸)═C(R⁹)—.-   In another embodiment of the compound of Formula (I), G¹ is selected    from the group consisting of:    -   phenyl,    -   pyrazole-3-yl,    -   benzothiazole-5-yl, benzothiazole-6-yl,    -   benzimidazole-5-yl, benzimidazole-6-yl,    -   benzoxazole-5-yl, benzoxazole-6-yl,    -   benzotriazole-5-yl, benzotriazole-6-yl,    -   benzoisoxazole-5-yl, benzoisoxazole-6-yl,    -   indole-5-yl, indole-6-yl,    -   2H-indazole-6-yl,    -   1H-indazole-3-yl, 1H-indazole-4-yl, 1H-indazole-5-yl,        1H-indazole-6-yl,    -   quinoline-6-yl, quinoline-7-yl,    -   quinazoline-4-yl,    -   2-oxindole-5-yl, 2-oxindole-6-yl,    -   2-(1H)-benzimidazolone-5-yl,    -   3-indazolinone-5-yl, and 3-indazolinone-6-yl,    -   wherein G¹ is optionally substituted 1-4 times with a        substituent selected from the group consisting of R^(b).-   In a further embodiment, G1 is unsubstituted or substituted with at    least one group selected from the group consisting of: halo, phenyl,    C₁₋₁₀ alkyl, piperazine-1-yl, 4-(C₁₋₁₀ alkyl)-piperazine-1-yl,    —C₁₋₁₀ alkoxy, —C₁₋₁₀ alkylene-OH, -haloalkyl, -cycloalkyl, —C₁₋₁₀    alkylene-cycloalkyl, morpholine-4-yl,    —C₁₋₁₀-alkylene-morpholine-4-yl, pyrrole-1-yl, -amino, —NH—(C₁₋₁₀    alkyl), —N(C₁₋₁₀ alkyl)₂, —NHC(O)—C₁₋₁₀ alkyl, —NHC(O)-(1-(C₁₋₁₀    alkyl)-piperidine-4-yl), —NHC(O)-phenyl, —NH—C₁₋₁₀    alkylene-morpholine-4-yl, —O—C₁₋₁₀ alkylene-morpholine-4-yl, and    —NH—C₁₋₁₀ alkylene-OH.-   In a further embodiment, L¹ is —NHC(O)— or —C(O)—NH— and G¹ is    1H-indazole-5-yl or 1H-indazole-6-yl, wherein G¹ is optionally    substituted 1-4 times with a substituent selected from the group    consisting of R^(b).-   In a further embodiment, G¹ is 1H-indazole-5-yl or 1H-indazole-6-yl,    wherein G¹ is unsubstituted or substituted at the 3-position with a    substituent selected from the group consisting of: halo, phenyl,    C₁₋₁₀ alkyl, piperazine-1-yl, 4-(C₁₋₁₀ alkyl)-piperazine-1-yl,    —C₁₋₁₀ alkoxy, —C₁₋₁₀ alkylene-OH, -haloalkyl, -cycloalkyl, —C₁₋₁₀    alkylene-cycloalkyl, morpholine-4-yl,    —C₁₋₁₀-alkylene-morpholine-4-yl, pyrrole-1-yl, -amino, —NH—(C₁₋₁₀    alkyl), —N(C₁₋₁₀ alkyl)₂, —NHC(O)—C₁₋₁₀ alkyl, —NHC(O)-(1-(C₁₋₁₀    alkyl)-piperidine-4-yl), —NHC(O)-phenyl, —NH—C₁₋₁₀    alkylene-morpholine-4-yl, —O—C₁₋₁₀ alkylene-morpholine-4-yl, and    —NH—C₁₋₁₀ alkylene-OH.-   In another embodiment, u is 1, A is a direct bond, and Q is selected    from the group consisting of:    -   4-(C₁₋₁₀ alkyl)-piperazine-1-yl,    -   piperadine-1-yl,    -   morpholine-4-yl,    -   —NH—C₁₋₁₀ alkyl,    -   —N—(C₁₋₁₀ alkyl)₂,    -   —N—(C₁₋₁₀ alkyl)(cycloalkyl), and    -   —NH-cycloalkyl.-   In an embodiment, u is zero and v is zero. In another embodiment, u    is 1 and v is zero.-   In another embodiment, u is zero and v is one.-   In another embodiment, u is zero and v is one, and R¹ is selected    from the group consisting of:    -   —C₁₋₁₀ alkyl,    -   -cycloalkyl,    -   —C₁₋₁₀ alkylene-cycloalkyl,    -   —C₁₋₁₀ haloalkyl,    -   -phenyl,    -   —O—C₁₋₁₀ alkyl,    -   —O-cycloalkyl, and    -   —O—Cl₁₋₁₀ haloalkyl.-   In another embodiment, X is —NH—, E is —NH—, v is zero, L¹ is    —NHC(O)— or —C(O)NH—, G¹ is 1H-indazol-6-yl or 1H-indazol-5-yl,    wherein G¹ optionally substituted 1-4 times with a substituent    selected from the group consisting of R^(b). In another embodiment,    G¹ is unsubstituted.-   In another embodiment, the compound of Formula (I) has the formula:    wherein    -   G¹, G², L¹, Q, and A are as defined above.-   In another embodiment, the compound of Formula (I) has the formula:    wherein    -   G¹, G², and Q are as defined above.-   In a further embodiment of Formula (Ib), Q is selected from the    group consisting of: 4-(C₁₋₁₀ alkyl)-piperazine-1-yl,    piperadine-1-yl, morpholine-4-yl, —N—(C₁₋₁₀ alkyl, —N—(C₁₋₁₀    alkyl)₂, —N—(C₁₋₁₀ alkyl)(cycloalkyl), and —NH-cycloalkyl.-   In a further embodiment of Formula (Ib), Q is selected from the    group consisting of: morpholine-4-yl, 4-methyl-piperazine-1-yl,    diethylamino, 2,6-dimethylmorpholine-4-yl,    (2-dimethylaminoethyl)-methylamino, 4-dimethylaminopiperidine-1-yl,    dipropylamino, bis-(2-methoxyethyl)amino, 4-hydroxypiperidine-1-yl,    ethyl-(2-methoxyethyl)amino, pyrrolidine-1-yl,    N-ethyl-N′-(2-methoxyethyl)amino, ethylpropylamino,    4-isopropylpiperazine-1-yl, and ethylmethylamino.-   In a further embodiment of Formula (Ib), G² is selected from the    group consisting of: phenyl, naphthyl, isoquinolin-3-yl,    pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl,    thiazole-2-yl, imidazole-2-yl, benzothiazole-2-yl, and    4,5,6,7-tetrahydro-thiazolo[5,4-c]-pyridine-2-yl, wherein G² is    optionally substituted 1-4 times with a substituent selected from    the group consisting of R^(b).-   In a further embodiment of Formula (Ib), G² is selected from the    group consisting of: phenyl and pyridine-2-yl, wherein G² is    unsubstituted or substituted with at least one substituent selected    from the group consisting of: methyl, methoxy, trifluoromethyl, and    trifluoromethoxy.-   In a further embodiment of Formula (Ib), G¹ is selected from the    group consisting of: phenyl, pyrazole-3-yl, benzothiazole-5-yl,    benzothiazole-6-yl, benzimidazole-5-yl, benzimidazole-6-yl,    benzoxazole-5-yl, benzoxazole-6-yl, benzotriazole-5-yl,    benzotriazole-6-yl, benzoisoxazole-5-yl, benzoisoxazole-6-yl,    indole-5-yl, indole-6-yl, 2H-indazole-6-yl, 1H-indazole-3-yl,    1H-indazole-4-yl, 1H-indazole-5-yl, 1H-indazole-6-yl,    quinoline-6-yl, quinoline-7-yl, quinazoline-4-yl, 2-oxindole-5-yl,    2-oxindole-6-yl, 2-(1H)-benzimidazolone-5-yl, 3-indazolinone-5-yl,    and 3-indazolinone-6-yl, wherein G¹ is optionally substituted 1-4    times with a substituent selected from the group consisting of    R^(b).-   In another embodiment, the compound of Formula (I) has the formula:    wherein G¹, G², and R¹ are as defined above.-   In a further embodiment of the compound of Formula (Ic), R¹ is    selected from the group consisting of: —C₁₋₁₀ alkyl, -cycloalkyl,    —C₁₋₁₀ alkylene-cycloalkyl, —C₁₋₁₀ haloalkyl, -phenyl, —O—C₁₋₁₀    alkyl, —O-cycloalkyl, and —O—C₁₋₁₀ haloalkyl.-   In a further embodiment of Formula (Ic), G² is selected from the    group consisting of: phenyl, naphthyl, isoquinolin-3-yl,    pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl,    thiazole-2-yl, imidazole-2-yl, benzothiazole-2-yl, and    4,5,6,7-tetrahydro-thiazolo[5,4-c]-pyridine-2-yl, wherein G is    optionally substituted 1-4 times with a substituent selected from    the group consisting of R^(b).-   In a further embodiment of Formula (Id), G¹ is selected from the    group consisting of: phenyl, pyrazole-3-yl, benzothiazole-5-yl,    benzothiazole-6-yl, benzimidazole-5-yl, benzimidazole-6-yl,    benzoxazole-5-yl, benzoxazole-6-yl, benzotriazole-5-yl,    benzotriazole-6-yl, benzoisoxazole-5-yl, benzoisoxazole-6-yl,    indole-5-yl, indole-6-yl, 2H-indazole-6-yl, 1H-indazole-3-yl,    1H-indazole-4-yl, 1H-indazole-5-yl, 1H-indazole-6-yl,    quinoline-6-yl, quinoline-7-yl, quinazoline-4-yl, 2-oxindole-5-yl,    2-oxindole-6-yl, 2-(1H)-benzimidazolone-5-yl, 3-indazolinone-5-yl,    and 3-indazolinone-6-yl, wherein G1 is optionally substituted 1-4    times with a substituent selected from the group consisting of    R^(b).

In the compounds of Formula (I), the various functional groupsrepresented should be understood to have a point of attachment at thefunctional group having the hyphen. In other words, in the case of—C₁₋₁₀ alkylene-aryl, it should be understood that the point ofattachment is the alkylene group; an example would be benzyl. In thecase of a group such as —C(O)—NH—C₁₋₁₀ alkylene-aryl, the point ofattachment is the carbonyl carbon.

The term “Aurora kinase inhibitor” or “inhibitor of Aurora kinase” isused to signify a compound having a structure as defined herein, whichis capable of interacting with an Aurora kinase and inhibiting itsenzymatic activity. Inhibiting Aurora kinase enzymatic activity meansreducing the ability of an Aurora kinase to phosphorylate a substratepeptide or protein. In various embodiments, such reduction of Aurorakinase activity is at least about 50%, at least about 75%, at leastabout 90%, at least about 95%, or at least about 99%. In variousembodiments, the concentration of Aurora kinase inhibitor required toreduce an Aurora kinase enzymatic activity is less than about 1 μM, lessthan about 500 nM, or less than about 100 nM.

In some embodiments, such inhibition is selective, i.e., the Aurorakinase inhibitor reduces the ability of an Aurora kinase tophosphorylate a substrate peptide or protein at a concentration that islower than the concentration of the inhibitor that is required toproduce another, unrelated biological effect, e.g., reduction of theenzymatic activity of a different kinase.

As used herein, the term “comprises” means “includes, but is not limitedto.”

Also included within the scope of the invention are the individualenantiomers of the compounds represented by Formula (I) above as well asany wholly or partially racemic mixtures thereof. The present inventionalso covers the individual enantiomers of the compounds represented byFormula (I) above as mixtures with diastereoisomers thereof in which oneor more stereocenters are inverted. Unless otherwise stated, structuresdepicted herein are also meant to include compounds which differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structure except for the replacement of ahydrogen atom by a deuterium or tritium, or the replacement of a carbonatom by a ¹³C— or ¹⁴C-enriched carbon are within the scope of theinvention.

In another aspect, the present invention provides a pharmaceuticallyacceptable salt, solvate, or prodrug of compounds of Formula (I). In anembodiment, the prodrug comprises a biohydrolyzable ester orbiohydrolyzable amide of a compound of Formula (I).

Examples of compounds of Formula (I) of the present invention havingpotentially useful biological activity are listed by name below inTable 1. The ability of compounds Formula (I) to inhibit Aurora kinaseactivity was established with representative compounds of Formula (I)listed in Table 1 using the peptide phosphorylation assay described inExample 102. The compounds of Formula (I) in Table 1 may inhibit AuroraKinase with an IC₅₀ of less than or equal to 1 microMolar (μM; 10⁻⁶ M).

Compounds that inhibit Aurora kinase activity are potentially useful intreating cell proliferative disorders. The compounds of Formula (I) ofthe present invention may therefore be particularly useful in thetreatment of cancer. TABLE 1 Ex. Name 12-(Isoquinolin-3-ylamino)-1H-benzimidazole-5-carboxylic acidbenzothiazol-6- ylamide 22-(Isoquinolin-3-ylamino)-1H-benzimidazole-5-carboxylic acid(1H-indazol-5-yl)- amide 32-(Pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid(1H-indazol-5-yl)- amide 42-(Pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (2-methyl-benzooxazol-5-yl)-amide 52-(Pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 6 2-(Pyridin-3-ylamino)-1H-benzimidazole-5-carboxylic acid(1H- indazol-6-yl)-amide 72-(Pyridin-2-ylamino)-1H-benzimidazole-4-carboxylic acidbenzothiazol-6-ylamide 82-(Pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-benzotriazol-5-yl)-amide 92-(2,4-Dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid (1-methyl-1H-indazol-5-yl)-amide 102-(2,4-Dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-5-yl)-amide 11 2-Phenylamino-1H-benzimidazole-5-carboxylicacid (1H-indazol-5- yl)-amide 122-Phenylamino-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 13 2-(Pyridin-4-ylamino)-1H-benzimidazole-5-carboxylic acid(1H- indazol-6-yl)-amide 142-(Thiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 15 2-Phenylamino-1H-benzimidazole-5-carboxylic acid(1H- benzotriazol-5-yl)-amide 162-(Pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1-methyl-1H-indazol-5-yl)-amide 172-(2-Chlorophenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 182-(4,5-Dimethylthiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 192-(2,4-Dichlorophenylamino)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 202-(Benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 212-(4-Phenylthiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 222-(2-Fluorophenylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 232-(2-Ethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 242-(2,4-Dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid(1H-benzotriazol-5-yl)-amide 252-(1-Isopropyl-1H-imidazol-2-ylamino)-3H-benzimidazole-5- carboxylicacid (1H-indazol-6-yl)-amide 262-(2,4-Dimethylphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 272-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 282-(4-Chlorophenylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 292-(Naphthalen-1-ylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 302-(2-tert-Butylphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 312-(Biphenyl-2-ylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 322-(2-Propylphenylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 332-(2,5-Dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 342-(2-Methoxyphenylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 352-(2-Trifluoromethylphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 362-(3-Methylpyridin-2-ylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 372-(2-Trifluoromethoxyphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 382-(3-Fluorophenylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 392-(4-Fluorophenylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 402-(3,5-Difluorophenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 412-(2-Butylphenylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 422-(3-Ethyl-6-methyl-pyridin-2-ylamino)-3H-benzimidazole-5- carboxylicacid (1H-indazol-6-yl)-amide 432-(5-Chloro-2-methyl-phenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 442-(3-Fluoro-2-methyl-phenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 452-(5-Fluoro-2-methyl-phenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 462-(3-Chloro-2-methyl-phenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 472-(1-Cyclopentyl-1H-imidazol-2-ylamino)-3H-benzimidazole-5- carboxylicacid (1H-indazol-6-yl)-amide 482-(2-Isopropylphenylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 492-(2-Isopropylphenylamino)-6-morpholin-4-yl-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 506-(4-Methylpiperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 512-(3,5-Difluorophenylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 522-(2,4-Dichlorophenylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 536-(4-Methylpiperazin-1-yl)-2-(thiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 546-Morpholin-4-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 552-(3,5-Difluorophenylamino)-6-morpholin-4-yl-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 562-(2,4-Dichlorophenylamino)-6-morpholin-4-yl-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 576-Piperidin-1-yl-2-(2-trifluoromethyl-phenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 586-(4-Methyl-piperazin-1-yl)-2-(3-methyl-pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 596-Morpholin-4-yl-2-(thiazol-2-ylamino)-1H-benzimidazole-5- carboxylicacid (1H-indazol-6-yl)-amide 602-(3-Methylpyridin-2-ylamino)-6-morpholin-4-yl-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 612-(1-Isopropyl-1H-imidazol-2-ylamino)-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 622-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 632-(1-Isopropyl-1H-imidazol-2-ylamino)-6-morpholin-4-yl-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 642-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-morpholin-4-yl-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 652-(2-Ethyl-2H-pyrazol-3-ylamino)-6-morpholin-4-yl-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 662-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid [3-(2-morpholin-4-yl-ethylamino)-1H-indazol-6-yl]-amide 672-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid [3-(3-morpholin-4-yl-propylamino)-1H-indazol-6-yl]-amide 682-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (3-methylamino-1H-indazol-6-yl)-amide 692-(Pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (3-amino-1H-indazol-6-yl)-amide 702-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid {3-[(1-methyl-piperidine-4-carbonyl)-amino]-1H-indazol-6-yl}-amide 712-(Pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (3-acetylamino-1H-indazol-6-yl)-amide 722-(2,4-Dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid (3-acetylamino-1H-indazol-6-yl)-amide 732-(2,4-Dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid (3-benzoylamino-1H-indazol-5-yl)-amide 742-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (3-methoxy-1H-indazol-6-yl)-amide 752-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid [3-(2-morpholin-4-yl-ethoxy)-1H-indazol-6-yl]-amide 762-(2,4-Dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid (3-morpholin-4-ylmethyl-1H-indazol-6-yl)-amide 772-(2,4-Dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid (3-methyl-1H-indazol-6-yl)-amide 782-(2-Ethylphenylamino)-3H-benzimidazole-5-carboxylic acid (3-chloro-1H-indazol-6-yl)-amide 792-[6-(1H-Indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester 802-(4,5,6,7-Tetrahydro-thiazolo[5,4-c]pyridin-2-ylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 812-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid [1-(2-hydroxy-ethyl)-1H-indazol-5-yl]-amide 822-(2-Cyclohexylphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 832-(3-Methylthiophen-2-ylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 84 1H-Indazole-6-carboxylic acid[2-(2-isopropyl-phenylamino)-3H- benzimidazol-5-yl]-amide 856-(4-Methylpiperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-5-yl)-amide 866-Morpholin-4-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-5-yl)-amide 874-[6-(1H-Indazol-6-ylcarbamoyl)-2-(2-trifluoromethylphenylamino)-3H-benzimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester 886-Piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 894-[6-(1H-Indazol-6-ylcarbamoyl)-2-(3-methylpyridin-2-ylamino)-3H-benzimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester 902-(3-Methylpyridin-2-ylamino)-6-piperazin-1-yl-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 912-(2,6-diethylphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol- 6-yl)-amide 926-diisobutylamino-2-(2-trifluoromethylphenylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 936-Diethylamino-2-(3-methylpyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 946-(2,6-Dimethylmorpholin-4-yl)-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 956-Diethylamino-2-(2-trifluoromethyl-phenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 966-[(2-dimethylaminoethyl)methylamino]-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 97 6-(4-Dimethylaminopiperidin-1-yl)-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 986-Dipropylamino-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 996-Dipropylamino-2-(3-methylpyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1006-[Bis-(2-methoxyethyl)amino]-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1016-(4-Hydroxypiperidin-1-yl)-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1026-[Ethyl-(2-methoxyethyl)amino]-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1036-[Bis-(2-methoxyethyl)amino]-2-(3-methylpyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1042-(3-Methylpyridin-2-ylamino)-6-pyrrolidin-1-yl-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1056-Pyrrolidin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1066-[(2-Dimethylaminoethyl)ethylamino]-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 1076-(4-Hydroxypiperidin-1-yl)-2-(3-methylpyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1086-[Ethyl-(2-methoxyethyl)amino]-2-(3-methylpyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1096-(Ethylpropylamino)-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1106-(Ethylpropylamino)-2-(3-methylpyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1116-(4-Isopropylpiperazin-1-yl)-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1126-(Ethylmethylamino)-2-(2-trifluoromethyl-phenylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1136-(Ethylmethylamino)-2-(3-methylpyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1146-(4-Isopropylpiperazin-1-yl)-2-(3-methylpyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1152-(3-Chloro-pyridin-2-ylamino)-6-diethylamino-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1166-Diethylamino-2-(3-trifluoromethyl-pyridin-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1172-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-diethylamino-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1182-Cyclohexylamino-6-diethylamino-1H-benzoimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 1192-Cyclopentylamino-6-diethylamino-1H-benzoimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 1202-(Bicyclo[2.2.1]hept-2-ylamino)-6-diethylamino-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1216-Diethylamino-2-isopropylamino-1H-benzoimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide 1226-Diethylamino-2-(3-ethyl-6-methyl-pyridin-2-ylamino)-3H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1236-Diethylamino-2-(2,5-difluoro-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1246-Diethylamino-2-(3,5-difluoro-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1252-(2-Chloro-5-trifluoromethyl-phenylamino)-6-diethylamino-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1266-Diethylamino-2-(2-trifluoromethoxy-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1273-[6-Diethylamino-5-(1H-indazol-6-ylcarbamoyl)-1H-benzoimidazol-2-ylamino]-benzoic acid methyl ester 1286-Diethylamino-2-(2-isopropyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1292-(4-Chloro-phenylamino)-6-diethylamino-1H-benzoimidazole-5- carboxylicacid (1H-indazol-6-yl)-amide 1302-(2,4-Dichloro-phenylamino)-6-diethylamino-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1316-Diethylamino-2-(2,6-difluoro-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1326-Diethylamino-2-(2-methoxy-phenylamino)-1H-benzoimidazole-5- carboxylicacid (1H-indazol-6-yl)-amide 1336-Diethylamino-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1342-(Bicyclo[2.2.1]hept-2-ylamino)-6-diethylamino-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1356-Diethylamino-2-isopropylamino-1H-benzoimidazole-5-carboxylic acidbenzothiazol-6-ylamide 1366-Diethylamino-2-(2,5-difluoro-phenylamino)-3H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1376-Diethylamino-2-(3,5-difluoro-phenylamino)-3H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1382-(2,4-Dichloro-phenylamino)-6-diethylamino-3H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1396-Diethylamino-2-(2-trifluoromethoxy-phenylamino)-3H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1406-Diethylamino-2-(2-isopropyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1416-(4-Methyl-piperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1426-(4-Methyl-piperazin-1-yl)-2-(3-methyl-pyridin-2-ylamino)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1436-Morpholin-4-yl-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1442-(3-Methyl-pyridin-2-ylamino)-6-morpholin-4-yl-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1456-(3,5-Dimethyl-piperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1466-(2-Methoxyethylamino)-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1476-(2-Methoxy-ethylamino)-2-(3-methyl-pyridin-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1486-(4-Methyl-piperazin-1-yl)-2-(2-trifluoromethyl-benzylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1492-Benzylamino-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1502-(Cyclohexylmethyl-amino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1512-Cyclopentylamino-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1522-((1S,2S,4R)-Bicyclo[2.2.1]hept-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1532-(Adamantan-1-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1546-Propylamino-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 155{1-[6-(1H-Indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperidin-4-yl}-carbamic acidtert-butyl ester 1566-(4-Amino-piperidin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amidetrihydrochloride 157{1-[6-(1H-Indazol-6-ylcarbamoyl)-2-(3-methyl-pyridin-2-ylamino)-3H-benzoimidazol-5-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester158 6-(4-Amino-piperidin-1-yl)-2-(3-methyl-pyridin-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amidetrihydrochloride 159[5-(1H-Indazol-6-ylethynyl)-1H-benzoimidazol-2-yl]-(2-trifluoromethyl-phenyl)-amine 1606-Dimethylamino-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1616-Dimethylamino-2-(3-methyl-pyridin-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1626-(4-Methyl-piperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid benzothiazol-5-ylamide 1634-[6-(Benzothiazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperazine-1-carboxylic acidtert-butyl ester 1646-Piperazin-1-yl-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide trihydrochloride165 4-[6-(Benzothiazol-6-ylcarbamoyl)-2-(3-methyl-pyridin-2-ylamino)-3H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester 1662-(3-Methyl-pyridin-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide trihydrochloride 1672-(2-Trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acidbenzothiazol-6-ylamide 1686-Piperazin-1-yl-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (5-methyl-1H-indazol-6-yl)-amide 1694-[2-((1S,2S,4R)Bicyclo[2.2.1]hept-2-ylamino)-6-(1H-indazol-6-ylcarbamoyl)-3H-benzoimidazol-5-yl]-piperazine-1-carboxylic acidtert-butyl ester 1702-((1S,2S,4R)Bicyclo[2.2.1]hept-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amidetrihydrochloride 1716-Chloro-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1722-((1S,2S,4R)-Bicyclo[2.2.1]hept-2-ylamino)-6-chloro-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1736-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 174 {4-[6-(1H-Indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperazin-1-yl}-acetic acid 1756-(4-Dimethylsulfamoyl-piperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 176{6-[5-(1H-Indazol-6-yl)-1H-imidazol-2-yl]-1H-benzoimidazol-2-yl}-(2-trifluoromethyl-phenyl)-amine 1776-(2-Dimethylamino-ethylsulfanyl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1785-Ethyl-8-(1H-indazol-6-yl)-2-(2-trifluoromethyl-phenylamino)-5,6,7,8-tetrahydro-3H-1,3,5,8-tetraaza-cyclohepta[f]inden-9-one 1796-Imidazol-1-yl-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1802-(2-Trifluoromethyl-phenylamino)-benzooxazole-5-carboxylic acid(1H-indazol-6-yl)-amide 1812-(1-Benzyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1824-[2-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(1H-indazol-6-ylcarbamoyl)-3H-benzoimidazol-5-yl]-piperazine-1-carboxylic acidtert-butyl ester 1832-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amidetrihydrochloride 1842-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(4-isopropyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1852-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(4-ethyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1862-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-[(2-dimethylaminoethyl)-methyl-amino]-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1872-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(4-methyl-[1,4]diazepan-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1882-(1-Cyclohexyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1892-(1-Methyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1902-(1-Cyclohexylmethyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1912-(1-Isobutyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1922-(1-Cyclobutyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1932-[1-(1-Ethyl-propyl)-1H-imidazol-2-ylamino]-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1942-(1-Butyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1952-[1-(2-Methoxy-ethyl)-1H-imidazol-2-ylamino]-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1962-(1-Ethyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 1972-[1-(2-Methoxy-ethyl)-1H-imidazol-2-ylamino]-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1982-(1-Ethyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 1992-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-5-yl)-amide 2002-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-benzotriazol-5-yl)- amide201 2-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide 2022-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (2-oxo-2,3-dihydro-1H-indol-5-yl)-amide 2032-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indol-6-yl)-amide 2042-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (3H-benzoimidazol-5-yl)- amide205 2-(1-Cyclopentyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid benzothiazol-5-ylamide 2066-(4-Methyl-piperazin-1-yl)-2-(1-thietan-3-yl-1H-imidazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)- amide207 2-Amino-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide trihydrobromide 2082-(3-cyclopentyl-3-ethylureido)-6-(4-methyl-piperazin-1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 2092-Mercapto-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5- carboxylicacid (1H-indazol-6-yl)-amide 2102-(1-Cyclopentyl-1H-benzimidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide 211[6-(1H-Indazol-6-yloxy)-1H-benzimidazol-2-yl]-(2-trifluoromethyl-phenyl)-amine 212{5-[2-(1H-indazol-6-yl)-ethyl]-1H-benzimidazol-2-yl}-(2-trifluoromethylphenyl)amine 2133-[6-Diethylamino-5-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-benzoic acid 2143-[5-(Benzothiazol-6-ylcarbamoyl)-6-diethylamino-1H-benzoimidazol-2-ylamino]-benzoic acid methyl ester 2153-[5-(Benzothiazol-6-ylcarbamoyl)-6-diethylamino-1H-benzoimidazol-2-ylamino]-benzoic acid

In another aspect, the present invention comprises a pharmaceuticalcomposition comprising the compound of Formula (I) and apharmaceutically acceptable carrier, excipient, diluent, or a mixturethereof. The present invention further provides uses of the compound ofFormula (I) for inhibiting Aurora kinase activity and for treatingAurora kinase-mediated disorders.

As used herein, the term “lower” refers to a group having between oneand six carbons.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having from one to ten carbon atoms, optionally substitutedand multiple degrees of substitution being allowed. Examples of “alkyl”as used herein include, but are not limited to, methyl, n-butyl,t-butyl, n-pentyl, isobutyl, and isopropyl, and the like.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted and multiple degrees of substitution beingallowed. Examples of “alkylene” as used herein include, but are notlimited to, methylene, ethylene, and the like.

As used herein, the term “alkyline” refers to a straight or branchedchain trivalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted and multiple degrees of substitution beingallowed. Examples of “alkyline” as used herein include, but are notlimited to, methine, ethyline, and the like.

As used herein, the term “alkenyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon doublebond, optionally substituted and multiple degrees of substitution beingallowed. Examples of “alkenyl” as used herein include, but are notlimited to, 3,3-dimethyl-but-1-phenyl, 4-hex-1-phenyl, and the like.

As used herein, the term “alkenylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon-carbon double bonds, optionally substituted andmultiple degrees of substitution being allowed. Examples of “alkenylene”as used herein include, but are not limited to, ethene-1,2-diyl,propene-1,3-diyl, methylene-1,1-diyl, and the like.

As used herein, the term “alkynyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon triplebond, optionally substituted and multiple degrees of substitution beingallowed. Examples of “alkynyl” as used herein include, but are notlimited to, 4-hex-1 ynyl, 3,3-dimethyl-but-1ynyl, and the like.

As used herein, the term “alkynylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon-carbon triple bonds, optionally substituted andmultiple degrees of substitution being allowed. Examples of “alkynylene”as used herein include, but are not limited to, ethyne-1,2-diyl,propyne-1,3-diyl, and the like.

As used herein, the terms “haloaliphatic”, “haloalkyl”, “haloalkenyl”and “haloalkoxy” refer to an aliphatic, alkyl, alkenyl or alkoxy group,as the case may be, substituted with one or more halogen atoms.

As used herein, “cycloalkyl” refers to a non-aromatic alicyclichydrocarbon group and optionally possessing one or more degrees ofunsaturation, having from three to twelve carbon atoms, optionallysubstituted and multiple degrees of substitution being allowed. Examplesof “cycloalkyl” as used herein include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and the like.

As used herein, the term “cycloalkylene” refers to an non-aromaticalicyclic divalent hydrocarbon radical having from three to twelvecarbon atoms and optionally possessing one or more degrees ofunsaturation, optionally substituted with substituents and multipledegrees of substitution being allowed. Examples of “cycloalkylene” asused herein include, but are not limited to, cyclopropyl-1,1-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, cyclooctyl-1,5-diyl, and thelike.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a non-aromatic three to twelve-membered heterocyclic ringoptionally possessing one or more degrees of unsaturation, containingone or more heteroatomic substitutions selected from S, SO, SO₂, O, orN, optionally substituted and multiple degrees of substitution beingallowed. Such a ring may be optionally fused to from one to three ofanother “heterocyclic” ring(s) or cycloalkyl ring(s). Examples of“heterocyclyl” include, but are not limited to, tetrahydrofuran,1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine,piperazine, and the like.

As used herein, the term “heterocyclylene” refers to a non-aromaticthree to twelve-membered heterocyclic ring diradical optionally havingone or more degrees of unsaturation containing one or more heteroatomsselected from S, SO, SO₂, O, or N, optionally substituted and multipledegrees of substitution being allowed. Such a ring may be optionallyfused to from one to three benzene rings or to one to three of another“heterocyclic” rings or cycloalkyl rings. Examples of “heterocyclylene”include, but are not limited to, tetrahydrofuran-2,5-diyl,morpholine-2,3-diyl, pyran-2,4-diyl, 1,4-dioxane-2,3-diyl,1,3-dioxane-2,4-diyl, piperidine-2,4-diyl, piperidine-1,4-diyl,pyrrolidine-1,3-diyl, morpholine-2,4-diyl, piperazine-1,4-diyl, and thelike.

As used herein, the term “aryl” refers to a benzene ring or to benzenering fused to one to three benzene rings, optionally substituted andmultiple degrees of substitution being allowed. Examples of arylinclude, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl,1-anthracenyl, and the like.

As used herein, the term “arylene” refers to a benzene ring diradical orto a benzene ring system diradical fused to one to three optionallysubstituted benzene rings, optionally substituted and multiple degreesof substitution being allowed. Examples of “arylene” include, but arenot limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and the like.

As used herein, the term “heteroaryl” refers to a five- toseven-membered aromatic ring, or to a polycyclic (up to three rings)aromatic ring, containing one or more nitrogen, oxygen, or sulfurheteroatoms, where N-oxides and sulfur monoxides and sulfur dioxides arepermissible heteroaromatic substitutions, optionally substituted andmultiple degrees of substitution being allowed. For polycyclicheteroaryl aromatic ring systems, one or more of the rings may containone or more heteroatoms. Examples of “heteroaryl” used herein include,but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole,triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole,thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine,quinoline, isoquinoline, quinazoline, benzofuran, benzothiophene,indole, and indazole, and the like.

As used herein, the term “heteroarylene” refers to a five- toseven-membered aromatic ring diradical, or to a polycyclic (up to threerings) heterocyclic aromatic ring diradical, containing one or morenitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfurmonoxides and sulfur dioxides are permissible heteroaromaticsubstitutions, optionally substituted and multiple degrees ofsubstitution being allowed. For polycyclic aromatic ring systemdiradicals, one or more of the rings may contain one or moreheteroatoms. Examples of “heteroarylene” used herein include, but arenot limited to, furan-2,5-diyl, thiophene-2,4-diyl,1,3,4-oxadiazole-2,5-diyl, 1,3,4-thiadiazole-2,5-diyl,1,3-thiazole-2,4-diyl, 1,3-thiazole-2,5-diyl, pyridine-2,4-diyl,pyridine-2,3-diyl, pyridine-2,5-diyl, pyrimidine-2,4-diyl,quinoline-2,3-diyl, and the like.

As used herein, the term “fused cycloalkylaryl” refers to one or twocycloalkyl groups fused to an aryl group, the aryl and cycloalkyl groupshaving two atoms in common, and wherein the aryl group is the point ofsubstitution. Examples of “fused cycloalkylaryl” used herein include5-indanyl, 5,6,7,8-tetrahydro-2-naphthyl,

and the like.

As used herein, the term “fused cycloalkylarylene” refers to a fusedcycloalkylaryl, wherein the aryl group is divalent. Examples include

and the like.

As used herein, the term “fused arylcycloalkyl” refers to one or twoaryl groups fused to a cycloalkyl group, the cycloalkyl and aryl groupshaving two atoms in common, and wherein the cycloalkyl group is thepoint of substitution. Examples of “fused arylcycloalkyl” used hereininclude 1-indanyl, 2-indanyl, 9-fluorenyl,1-(1,2,3,4-tetrahydronaphthyl),

and the like.

As used herein, the term “fused arylcycloalkylene” refers to a fusedarylcycloalkyl, wherein the cycloalkyl group is divalent. Examplesinclude 9,1-fluorenylene,

and the like.

As used herein, the term “fused heterocyclylaryl” refers to one or twoheterocyclyl groups fused to an aryl group, the aryl and heterocyclylgroups having two atoms in common, and wherein the aryl group is thepoint of substitution. Examples of “fused heterocyclylaryl” used hereininclude 3,4-methylenedioxy-1-phenyl,

and the like

As used herein, the term “fused heterocyclylarylene” refers to a fusedheterocyclylaryl, wherein the aryl group is divalent. Examples include

and the like.

As used herein, the term “fused arylheterocyclyl” refers to one or twoaryl groups fused to a heterocyclyl group, the heterocyclyl and arylgroups having two atoms in common, and wherein the heterocyclyl group isthe point of substitution. Examples of “fused arylheterocyclyl” usedherein include 2-(1,3-benzodioxolyl),

and the like.

As used herein, the term “fused arylheterocyclylene” refers to a fusedarylheterocyclyl, wherein the heterocyclyl group is divalent. Examplesinclude

and the like.

As used herein, the term “fused cycloalkylheteroaryl” refers to one ortwo cycloalkyl groups fused to a heteroaryl group, the heteroaryl andcycloalkyl groups having two atoms in common, and wherein the heteroarylgroup is the point of substitution. Examples of “fusedcycloalkylheteroaryl” used herein include 5-aza-6-indanyl,

and the like.

As used herein, the term “fused cycloalkylheteroarylene” refers to afused cycloalkylheteroaryl, wherein the heteroaryl group is divalent.Examples include

and the like.

As used herein, the term “fused heteroarylcycloalkyl” refers to one ortwo heteroaryl groups fused to a cycloalkyl group, the cycloalkyl andheteroaryl groups having two atoms in common, and wherein the cycloalkylgroup is the point of substitution. Examples of “fusedheteroarylcycloalkyl” used herein include 5-aza-1-indanyl,

and the like.

As used herein, the term “fused heteroarylcycloalkylene” refers to afused heteroarylcycloalkyl, wherein the cycloalkyl group is divalent.Examples include

and the like.

As used herein, the term “fused heterocyclylheteroaryl” refers to one ortwo heterocyclyl groups fused to a heteroaryl group, the heteroaryl andheterocyclyl groups having two atoms in common, and wherein theheteroaryl group is the point of substitution. Examples of “fusedheterocyclylheteroaryl” used herein include1,2,3,4-tetrahydro-beta-carbolin-8-yl,

and the like.

As used herein, the term “fused heterocyclylheteroarylene” refers to afused heterocyclylheteroaryl, wherein the heteroaryl group is divalent.Examples include

and the like.

As used herein, the term “fused heteroarylheterocyclyl” refers to one ortwo heteroaryl groups fused to a heterocyclyl group, the heterocyclyland heteroaryl groups having two atoms in common, and wherein theheterocyclyl group is the point of substitution. Examples of “fusedheteroarylheterocyclyl” used herein include-5-aza-2,3-dihydrobenzofuran-2-yl,

and the like.

As used herein, the term “fused heteroarylheterocyclylene” refers to afused heteroarylheterocyclyl, wherein the heterocyclyl group isdivalent. Examples include

and the like.

As used herein, the term “direct bond”, where part of a structuralvariable specification, refers to the direct joining of the substituentsflanking (preceding and succeeding) the variable taken as a “directbond”. Where two or more consecutive variables are specified each as a“direct bond”, those substituents flanking (preceding and succeeding)those two or more consecutive specified “direct bonds” are directlyjoined.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl.

As used herein, the term “alkenyloxy” refers to the group R_(a)O—, whereR_(a) is alkenyl.

As used herein, the term “alkynyloxy” refers to the group R_(a)O—, whereR_(a) is alkynyl.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkyl.

As used herein, the term “alkenylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkenyl.

As used herein, the term “alkynylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkynyl.

As used herein, the term “alkylsulfinyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl.

As used herein, the term “alkenylsulfinyl” refers to the groupR_(a)S(O)—, where R_(a) is alkenyl.

As used herein, the tern “alkynylsulfinyl” refers to the groupR_(a)S(O)—, where R_(a) is alkynyl.

As used herein, the term “alkylsulfonyl” refers to the group R_(a)SO₂—,where R_(a) is alkyl.

As used herein, the term “alkenylsulfonyl” refers to the groupR_(a)SO₂—, where R_(a) is alkenyl.

As used herein, the term “alkynylsulfonyl” refers to the groupR_(a)SO₂—, where R_(a) is alkynyl.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R_(a) is heteroaryl.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is alkyl.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R_(a) is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, orheterocyclyl.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution of one ormore hydrogens of the designated moiety with the named substituent orsubstituents, multiple degrees of substitution being allowed unlessotherwise stated, provided that the substitution results in a stable orchemically feasible compound. A stable compound or chemically feasiblecompound is one in which the chemical structure is not substantiallyaltered when kept at a temperature from about −80° C. to about +40° C.,in the absence of moisture or other chemically reactive conditions, forat least a week, or a compound which maintains its integrity long enoughto be useful for therapeutic or prophylactic administration to apatient. The phrase “one or more substituents”, as used herein, refersto a number of substituents that equals from one to the maximum numberof substituents possible based on the number of available bonding sites,provided that the above conditions of stability and chemical feasibilityare met.

As used herein, the terms “contain” or “containing” can refer to in-linesubstitutions at any position along the above defined alkyl, alkenyl,alkynyl or cycloalkyl substituents with one or more of any of O, S, SO,SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—,—CH₂—NH—CH₃ and so forth.

Whenever the terms “alkyl” or “aryl” or either of their prefix rootsappear in a name of a substituent (e.g. arylalkoxyaryloxy) they shall beinterpreted as including those limitations given above for “alkyl” and“aryl”. Designated numbers of carbon atoms (e.g. C₁₋₁₀) shall referindependently to the number of carbon atoms in an alkyl, alkenyl oralkynyl or cyclic alkyl moiety or to the alkyl portion of a largersubstituent in which the term “alkyl” appears as its prefix root.

As used herein, the term “oxo” shall refer to the substituent ═O.

As used herein, the term “halogen” or “halo” refers iodine, bromine,chlorine or fluorine.

As used herein, the term “mercapto” refers to the substituent —SH.

As used herein, the term “carboxy” refers to the substituent —COOH.

As used herein, the term “cyano” refers to the substituent —CN.

As used herein, the term “aminosulfonyl” refers to the substituent—SO₂NH₂.

As used herein, the term “carbamoyl” refers to the substituent —C(O)NH₂.

As used herein, the term “sulfanyl” refers to the substituent —S—.

As used herein, the term “sulfinyl” refers to the substituent —S(O)—.

As used herein, the term “sulfonyl” refers to the substituent —S(O)₂—.

The compounds can be prepared according to the following reactionSchemes (in which variables are as defined before or are defined) usingreadily available starting materials, and reagents. In these reactions,it is also possible to make use of variants which are themselves knownto those of ordinary skill in this art, but are not mentioned in greaterdetail.

The present invention also provides a method for the synthesis ofcompounds useful as intermediates in the preparation of compounds ofFormula (I) along with methods for the preparation of compounds ofFormula (I). Unless otherwise specified, structural variables are asdefined for Formula (I).

As shown in Scheme I, diaminobenzoate (1) is reacted with isothiocyanate(6) by heating in a solvent such as, but not limited to, THF to providethiourea (2). Isothiocyanate (6) is either commercially available or isprepared from a corresponding amine (5) by reacting with1,1′-thiocarbonylimidazole in solvent such as, but not limited to, THF.The thiourea (2) is treated with a coupling reagent such as, but notlimited to, EDC to furnish aminobenzimidazole, which upon hydrolysis,yields carboxylic acid (3). The carboxylic acid (3) is then coupled withan amine in the presence of a coupling reagent such as, but not limitedto, HBTU to form amide (4).

Alternatively, the aminobenzimidazole (4) is also made as shown inScheme II. Carboxylic acid (7) is coupled with an amine in the presenceof a coupling reagent such as, but not limited to HBTU, to form an amide(8). The nitro group of intermediate (8) is then reduced underconditions such as, but not limited to, Pd/C under hydrogen atmosphereto provide diamine (9). The diamine (9) is then reacted with anisothiocyanate, as described for Scheme I, to provide thiourea, whichupon treatment with coupling reagent such as, but not limited to, EDC toyield aminobenzimidazole (4).

As shown in Scheme III, benzoic acid chloride derivative (10), which isobtained from the corresponding carboxylic acid by heating with areagent such as, but not limited to, oxalyl chloride, is coupled with anamine in the presence of a base such as, but not limited to, pyridine toform an amide (11). Amide (11) is then converted into nitroaniline (12)by heating with ammonium hydroxide in a solvent such as, but not limitedto, DCM. Nitroaniline (12), upon heating with a nucleophile such as, butnot limited to, an amine under neat conditions or in the presence of asolvent, is transformed into intermediate (13). The nitro group ofintermediate (13) is then reduced under conditions such as, but notlimited to, Pd/C under hydrogen atmosphere to provide diamine (14). Thediamine (14) is then reacted with an isothiocyanate, as described forScheme I, to provide thiourea, which upon treatment with couplingreagent such as, but not limited to, EDC to yield aminobenzimidazole(15).

The compounds of this invention are inhibitors of Aurora kinase. Thecompounds can be assayed in vitro for their ability to inhibit an Aurorakinase. In vitro assays include assays to determine inhibition of theability of an Aurora kinase to phosphorylate a substrate protein orpeptide. Alternate in vitro assays quantitate the ability of thecompound to bind to an Aurora kinase. Inhibitor binding may be measuredby radiolabelling the inhibitor prior to binding, isolating theinhibitor/Aurora kinase complex and determining the amount of radiolabelbound. Alternatively, inhibitor binding may be determined by running acompetition experiment in which new inhibitors are incubated with Aurorakinase bound to a known radioligand. The compounds also can be assayedfor their ability to affect cellular or physiological functions mediatedby Aurora kinase activity. Assays for each of these activities aredescribed in the Examples and/or are known in the art.

In general, embodiments of the present invention useful forpharmaceutical applications may have inhibitory potencies (IC₅₀'s) for aprotein of interest of below about 10 μM. In an embodiment, embodimentsof the present invention useful for pharmaceutical applications may havean IC₅₀ for a protein of interest of below about 1 μM. For particularapplications, lower inhibitory potencies may be useful. Thus, in anotherembodiment, compounds of the present invention may inhibit Aurora kinasewith an IC₅₀ in a range of less than 100 nM. In another embodiment,compounds of the present invention may inhibit Aurora kinase withinhibitory potencies (IC₅₀'s) of between 0.1 nM and 100 nM.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) wherein the compound ofFormula (I) is administered in a dose of less than 1,000 mg/kg of bodyweight per day. In another embodiment, the present invention provides apharmaceutical composition comprising a compound of Formula (I) whereinthe compound of Formula (I) is administered in a dose of less than 100mg/kg of body weight per day. In another embodiment, the presentinvention provides a pharmaceutical composition comprising a compound ofFormula (I) wherein the compound of Formula (I) is administered in adose of less than 10 mg/kg of body weight per day.

Embodiments of the compounds of the present invention demonstrateutility as inhibitors of Aurora kinase activity or as inhibitors of cellproliferation. Embodiments of the invention described herein areadditionally directed to pharmaceutical compositions and methods ofinhibiting Aurora kinase in a subject, which methods compriseadministering to a subject in need of inhibition of Aurora kinaseactivity a therapeutically effective amount of a compound of Formula(I), defined above, as a single or polymorphic crystalline form orforms, an amorphous form, a single enantiomer, a racemic mixture, asingle stereoisomer, a mixture of stereoisomers, a singlediastereoisomer, a mixture of diastereoisomers, a solvate, apharmaceutically acceptable salt, a solvate, a prodrug, abiohydrolyzable ester, or a biohydrolyzable amide thereof.

In an embodiment, the invention provides a method for inhibiting Aurorakinase activity comprising contacting a cell in which inhibition ofAurora kinase is desired with an Aurora kinase inhibitor of Formula (I).In an embodiment, the Aurora kinase inhibitor interacts with and reducesthe activity of fewer than all Aurora kinase enzymes in the cell. Wherea compound of the present invention selectively acts as an inhibitor ofAurora kinase in preference to one or more other kinases, treatment of asubject with such a selective compound may possess advantage in thetreatment of cancer in the subject over non-specific kinase inhibitors.Thus, in another embodiment, the present invention provides a method forselectively inhibiting Aurora kinase activity in the presence of one ormore other kinases comprising contacting a cell in which inhibition ofAurora kinase is desired with an Aurora kinase inhibitor of Formula (I).

The method according to this aspect of the invention causes aninhibition of cell proliferation of the contacted cells. The phrase“inhibiting cell proliferation” is used to denote an ability of aninhibitor of Aurora kinase to inhibit cell number or cell growth incontacted cells as compared to cells not contacted with the inhibitor.An assessment of cell proliferation can be made by counting cells usinga cell counter, by measuring uptake of a labeled nucleotide ornucleotide analog, or by an assay of cell viability. Where the cells arein a solid growth (e.g., a solid tumor or organ), such an assessment ofcell proliferation can be made by measuring the growth, e.g., withcalipers, and comparing the size of the growth of contacted cells withnon-contacted cells.

The growth of cells contacted with an inhibitor may be retarded by atleast about 50% as compared to growth of non-contacted cells. In variousembodiments, cell proliferation of contacted cells is inhibited by atleast about 75% as compared to non-contacted cells. In some embodiments,the phrase “inhibiting cell proliferation” includes a reduction in thenumber of contacted cells, as compared to non-contacted cells. Thus, aninhibitor of Aurora kinase that inhibits cell proliferation in acontacted cell may induce the contacted cell to undergo growthretardation, to undergo growth arrest, to undergo programmed cell death(i.e., apoptosis), or to undergo necrotic cell death.

Subjects may include, but are not limited to, horses, cows, sheep, pigs,mice, dogs, cats, primates such as chimpanzees, gorillas, rhesusmonkeys, and, humans. In an embodiment, a subject is a human in need ofinhibition of Aurora kinase activity.

The pharmaceutical compositions containing a compound of the inventionmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous, or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anyknown method, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxicpharmaceutically-acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques to form osmotic therapeutic tablets forcontrolled release.

Formulations for oral use may also be presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or a softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions may contain the active compounds in an admixturewith excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyl-eneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as a liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring, and coloringagents may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oil, or a mineral oil, for example aliquid paraffin, or a mixture thereof. Suitable emulsifying agents maybe naturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known methods using suitable dispersing orwetting agents and suspending agents described above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, sterile water forinjection (SWFI), Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conveniently employed assolvent or suspending medium. For this purpose, any bland fixed oil maybe employed using synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid find use in the preparation of injectables.

Thus, in another embodiment, the present invention provides apharmaceutical formulation solution comprising a compound of Formula(I). or a salt thereof.

A solution of the invention may be provided in a sealed container,especially one made of glass, either in a unit dosage form or in amultiple dosage form.

Any pharmaceutically acceptable salt of a compound of Formula (I) may beused for preparing a solution of the invention. Examples of suitablesalts may be, for instance, the salts with mineral inorganic acids suchas hydrochloric, hydrobromic, sulfuric, phosphoric, nitric and the like,and the salts with certain organic acids such as acetic, succinic,tartaric, ascorbic, citric, glutamic, benzoic, methanesulfonic,ethanesulfonic and the like. In an embodiment, the compound of Formula(I) is a hydrochloric acid salt including a mono, di, ortrihydrochloride.

Any solvent which is pharmaceutically acceptable and which is able todissolve the compound of Formula (I) or a pharmaceutically acceptablesalt thereof may be used. The solution of the invention may also containone or more additional components such as a co-solubilizing agent (whichmay be the same as a solvent), a tonicity adjustment agent, astabilizing agent, a preservative, or mixtures thereof. Examples ofsolvents, co-solubilizing agents, tonicity adjustment agents,stabilizing agents and preservatives which may suitable for a solutionformulation are described below.

Suitable solvents and co-solubilizing agents may include, but are notlimited to, water; sterile water for injection (SWFI); physiologicalsaline; alcohols, e.g. ethanol, benzyl alcohol and the like; glycols andpolyalcohols, e.g. propyleneglycol, glycerin and the like; esters ofpolyalcohols, e.g. diacetine, triacetine and the like; polyglycols andpolyethers, e.g. polyethyleneglycol 400, propyleneglycol methylethersand the like; dioxolanes, e.g. isopropylidenglycerin and the like;dimethylisosorbide; pyrrolidone derivatives, e.g. 2-pyrrolidone,N-methyl-2-pyrrolidone, polyvinylpyrrolidone (co-solubilizing agentonly) and the like; polyoxyethylenated fatty alcohols; esters ofpolyoxyethylenated fatty acids; polysorbates, e.g., Tween™,polyoxyethylene derivatives of polypropyleneglycols, e.g., Pluronics™.

Suitable tonicity adjustment agents may include, but are not limited to,pharmaceutically acceptable inorganic chlorides, e.g. sodium chloride;dextrose; lactose; mannitol; sorbitol and the like.

Preservatives suitable for physiological administration may be, forinstance, esters of parahydroxybenzoic acid (e.g., methyl, ethyl, propyland butyl esters, or mixtures of them), chlorocresol and the like.

Suitable stabilizing agents include, but are not limited to,monosaccharides (e.g., galactose, fructose, and fucose), disaccharides(e.g., lactose), polysaccharides (e.g., dextran), cyclicoligosaccharides (e.g., alpha-, beta-, gamma-cyclodextrin), aliphaticpolyols (e.g., mannitol, sorbitol, and thioglycerol), cyclic polyols(e.g. inositol) and organic solvents (e.g., ethyl alcohol and glycerol).

The above mentioned solvents and co-solubilizing agents, tonicityadjustment agents, stabilizing agents and preservatives can be usedalone or as a mixture of two or more of them in a solution formulation.

In an embodiment, a pharmaceutical solution formulation may comprise acompound of Formula (I) or a pharmaceutically acceptable salt thereof,SWFI, and an agent selected from the group consisting of sodium chloridesolution (i.e., physiological saline), dextrose, mannitol, or sorbitol,wherein the agent is in an amount of less than or equal to 5%. The pH ofsuch a formulation may also be adjusted to improve the storage stabilityusing a pharmaceutically acceptable acid or base.

In the solutions of the invention the concentration of the compound ofFormula (I) or a pharmaceutically acceptable salt thereof may be lessthan 100 mg/mL, or less than 50 mg/mL, or less than 10 mg/mL, or lessthan 10 mg/mL and greater than 0.01 mg/mL, or between 0.5 mg/mL and 5mg/mL, or between 1 mg/mL and 3 mg/mL.

Suitable packaging for the pharmaceutical solution formulations may beall approved containers intended for parenteral use, such as plastic andglass containers, ready-to-use syringes and the like. In an embodiment,the container is a sealed glass container, e.g. a vial or an ampoule. Ahermetically sealed glass vial is particularly preferred.

According to an embodiment of the present invention, there is provided,in a sealed glass container, a sterile, injectable solution comprising acompound of Formula (I) or a pharmaceutically acceptable salt thereof ina physiologically acceptable solvent, and which has a pH of from 2.5 to3.5. For solution formulations, various compounds of the presentinvention may be more soluble or stable for longer periods in solutionsat a pH lower than 6. Further, acid salts of the compounds of thepresent invention may be more soluble in aqueous solutions than theirfree base counter parts, but when the acid salts are added to aqueoussolutions the pH of the solution may be too low to be suitable foradministration. Thus, solution formulations having a pH above pH 4.5 maybe combined prior to administration with a diluent solution of pHgreater than 7 such that the pH of the combination formulationadministered is pH 4.5 or higher. In one embodiment, the diluentsolution comprises a pharmaceutically acceptable base such as sodiumhydroxide. In another embodiment, the diluent solution is at pH ofbetween 10 and 12. In another embodiment, the pH of the combinedformulation administered is greater than 5.0. In another embodiment, thepH of the combined formulation administered is between pH 5.0 and 7.0.

The invention also provides a process for producing a sterile solutionwith a pH of from 2.5 to 3.5 which process comprises dissolving acompound of Formula (I) or a pharmaceutically acceptable salt thereof ina pharmaceutically acceptable solvent. Where a pharmaceuticallyacceptable acid salt of a compound of Formula (I) is used the pH of thesolution may be adjusted using a pharmaceutically acceptable base orbasic solution adding a physiologically acceptable acid or buffer toadjust the pH within a desired range. The method may further comprisepassing the resulting solution through a sterilizing filter.

One or more additional components such as co-solubilizing agents,tonicity adjustment agents, stabilizing agents and preservatives, forinstance of the kind previously specified, may be added to the solutionprior to passing the solution through the sterilizing filter.

Specific pharmaceutical solution formulations with different pH's andconcentrations are illustrated in the Examples which follow.

Thus, according to the invention there is also provided a method ofinhibiting the growth of a tumor or cancer, which comprisesadministering to a host suffering from said tumor or cancer aninjectable solution according to the invention containing the activedrug substance in an amount sufficient to inhibit the growth of saidtumor.

The injectable solutions of the invention may be administered by rapidintravenous injection or infusion according to a variety of possibledose schedules.

The compositions may also be in the form of suppositories for rectaladministration of the compounds of the invention. These compositions canbe prepared by mixing the drug with a suitable non-irritating excipientwhich is solid at ordinary temperatures but liquid at the rectaltemperature and will thus melt in the rectum to release the drug. Suchmaterials include cocoa butter and polyethylene glycols, for example.

For topical use, creams, ointments, jellies, solutions of suspensions,etc., containing the compounds of the invention are contemplated. Forthe purpose of this application, topical applications shall includemouth washes and gargles.

The compounds of the present invention may also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes may beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Also provided by the present invention are prodrugs of the invention.Pharmaceutically-acceptable salts of the compounds of the presentinvention, where a basic or acidic group is present in the structure,are also included within the scope of the invention. The term“pharmaceutically acceptable salts” refers to non-toxic salts of thecompounds of this invention which are generally prepared by reacting thefree base with a suitable organic or inorganic acid or by reacting theacid with a suitable organic or inorganic base. Representative saltsinclude the following salts: Acetate, Benzenesulfonate, Benzoate,Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium Edetate,Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride,Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate,Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine,Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isethionate,Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,Methylbromide, Methylnitrate, Methylsulfate, Monopotassium Maleate,Mucate, Napsylate, Nitrate, N-methylglucamine, Oxalate, Pamoate(Embonate), Palmitate, Pantothenate, Phosphate/diphosphate,Polygalacturonate, Potassium, Salicylate, Sodium, Stearate, Subacetate,Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide,Trimethylammonium and Valerate. When an acidic substituent is present,such as —COOH, there can be formed the ammonium, morpholinium, sodium,potassium, barium, calcium salt, and the like, for use as the dosageform. When a basic group is present, such as amino or a basic heteroarylradical, such as pyridyl, an acidic salt, such as hydrochloride,hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacetate,acetate, oxlate, maleate, pyruvate, malonate, succinate, citrate,tartarate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate,ethanesulfonate, picrate and the like, and include acids related to thepharmaceutically-acceptable salts listed in the Journal ofPharmaceutical Science, 66, 2 (1977) p. 1-19.

Other salts which are not pharmaceutically acceptable may be useful inthe preparation of compounds of the invention and these form a furtheraspect of the invention.

In addition, some of the compounds of the present invention may formsolvates with water or common organic solvents. Such solvates are alsoencompassed within the scope of the invention.

Thus, in a further embodiment, there is provided a pharmaceuticalcomposition comprising a compound of the present invention, or apharmaceutically acceptable salt, solvate, or prodrug thereof, and apharmaceutically acceptable carrier, excipient, diluent, or mixturesthereof.

The pharmaceutical compositions of the present invention may be usefulin therapeutic applications relating to an Aurora kinase-mediateddisorder. As used herein, the term “Aurora kinase-mediated disorder”includes any disorder, disease or condition which is caused orcharacterized by an increase in Aurora kinase expression or activity, orwhich requires Aurora kinase activity. The term “Aurora kinase-mediateddisorder” also includes any disorder, disease or condition in whichinhibition of Aurora kinase activity is beneficial. Aurorakinase-mediated disorders include proliferative disorders. Non-limitingexamples of proliferative disorders include chronic inflammatoryproliferative disorders, e.g., psoriasis and rheumatoid arthritis andchronic pulmonary disease; proliferative ocular disorders, e.g.,diabetic retinopathy; benign proliferative disorders, e.g., hemangiomas;restenosis, artherosclerosis, angiogenisis, and cancer.

In an embodiment, the composition is formulated for administration to asubject having or at risk of developing or experiencing a recurrence ofan Aurora kinase-mediated disorder. In an embodiment, the pharmaceuticalcompositions of the invention are those formulated for oral,intravenous, or subcutaneous administration. However, any of the abovedosage forms containing a therapeutically effective amount of a compoundof the invention are within the bounds of routine experimentation andtherefore, within the scope of the instant invention. In someembodiments, the pharmaceutical composition of the invention may furthercomprise another therapeutic agent. In an embodiment, such othertherapeutic agent is one normally administered to a subject with thedisease or condition being treated.

As used herein, “therapeutically effective amount” is an amount of thecompound of Formula (I) sufficient to cause a detectable decrease inAurora kinase activity or the severity of an Aurora kinase-mediateddisorder. The amount of Aurora kinase inhibitor needed will depend onthe effectiveness of the inhibitor for the given cell type and thelength of time required to treat the disorder. It should also beunderstood that a specific dosage and treatment regimen for anyparticular subject will depend upon a variety of factors, including theactivity of the specific compound employed, the age, body weight,general health, sex, and diet of the patient, time of administration,rate of excretion, drug combinations, the judgment of the treatingphysician, and the severity of the particular disease being treated.

In another aspect, the invention provides a method for treating asubject having or at risk of developing or experiencing a recurrence ofan Aurora kinase-mediated disorder. The method comprises the step ofadministering to the subject a compound or pharmaceutical compositionaccording to the invention. The compounds and pharmaceuticalcompositions of the invention may be used to achieve a beneficialtherapeutic or prophylactic effect, for example, in a subject with aproliferative disorder, as discussed above, such as cancer.

As used herein, the term “cancer” refers to a cellular disordercharacterized by uncontrolled or dysregulated cell proliferation,decreased cellular differentiation, inappropriate ability to invadesurrounding tissue, and/or ability to establish new growth at ectopicsites. The term “cancer” includes, but is not limited to, solid tumorsand bloodborne tumors. The term “cancer” encompasses diseases of skin,tissues, organs, bone, cartilage, blood, and vessels. The term “cancer”further encompasses primary and metastatic cancers.

Non-limiting examples of solid tumors that can be treated by the methodsof the invention include pancreatic cancer; bladder cancer; colorectalcancer; breast cancer, including metastatic breast cancer; prostatecancer, including androgen-dependent and androgen-independent prostatecancer; renal cancer, including, e.g., metastatic renal cell carcinoma;hepatocellular cancer; lung cancer, including, e.g., non-small cell lungcancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinomaof the lung; ovarian cancer, including, e.g., progressive epithelial orprimary peritoneal cancer; cervical cancer; gastric cancer; esophagealcancer; head and neck cancer, including, e.g., squamous cell carcinomaof the head and neck; melanoma; neuroendocrine cancer, includingmetastatic neuroendocrine tumors; brain tumors, including, e.g., glioma,anaplastic oligodendroglioma, adult glioblastoma multiforme, and adultanaplastic astrocytoma; bone cancer; and soft tissue sarcoma.

In some other embodiments, the cancer is a hematologic malignancy.Non-limiting examples of hematologic malignancy include acute myeloidleukemia (AML); chronic myelogenous leukemia (CML), includingaccelerated CML and CML blast phase (CML-BP); acute lymphoblasticleukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease(HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma andmantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma(MN); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS),including refractory anemia (RA), refractory anemia with ringedsiderblasts (RARS), (refractory anemia with excess blasts (RAEB), andRAEB in transformation (RAEB-T); and myeloproliferative syndromes.

In some embodiments, the compound or composition of the invention isused to treat a cancer in which the activity of an Aurora kinase isamplified. In some embodiments, the compound or composition of theinvention is used to treat a patient having or at risk of developing orexperiencing a recurrence in a cancer selected from the group consistingof colorectal cancer, ovarian cancer, breast cancer, gastric cancer,prostate cancer, and pancreatic cancer. In certain embodiments, thecancer is selected from the group consisting of breast cancer,colorectal cancer, and pancreatic cancer.

In some embodiments, the Aurora kinase inhibitor of the invention isadministered in conjunction with another therapeutic agent. The othertherapeutic agent may also inhibit Aurora kinase or may operate by adifferent mechanism. In some embodiments, the other therapeutic agent isone that is normally administered to subject with the disease orcondition being treated. The Aurora kinase inhibitor of the inventionmay be administered with the other therapeutic agent in a single dosageform or as a separate dosage form. When administered as a separatedosage form, the other therapeutic agent may be administered prior to,at the same time as, or following administration of the Aurora kinaseinhibitor of the invention.

In some embodiments, the Aurora kinase inhibitor of the invention isadministered in conjunction with a therapeutic agent selected from thegroup consisting of cytotoxic agents, radiotherapy, immunotherapy, orother kinase inhibitors. Non-limiting examples of cytotoxic agents thatmay be suitable for use in combination with the Aurora kinase inhibitorsof the invention include: antimetabolites, including, e.g.,capecitibine, gemcitabine, 5-fluorouracil or 5-fluorouracil/leucovorin,fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin, andmethotrexate; topoisomerase inhibitors, including, e.g., etoposide,teniposide, camptothecin, topotecan, irinotecan, doxorubicin, anddaunorubicin; vinca alkaloids, including, e.g., vincristine andvinblastin; taxanes, including, e.g., paclitaxel and docetaxel; platinumagents, including, e.g., cisplatin, carboplatin, and oxaliplatin;antibiotics, including, e.g., actinomycin D, bleomycin, mitomycin C,adriamycin, daunorubicin, idarubicin, doxorubicin and pegylatedliposomal doxorubicin; alkylating agents such as melphalan,chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine,semustine, streptozocin, decarbazine, and cyclophosphamide; thalidomide;protein tyrosine kinase inhibitors, including, e.g., imatinib mesylate,erlotinib, and gefitinib; antibodies, including, e.g., trastuzumab,rituximab, cetuximab, and bevacizumab; mitoxantrone; dexamethasone;prednisone; and temozolomide.

EXAMPLES

The present invention may be further understood by reference to thefollowing non-limiting examples. Examples of compounds of the presentinvention and procedures that may be used to prepare and identify usefulcompounds of the present invention are described below.

Abbreviations used in the Examples are as follows:

Boc=tert-butoxycarbonyl

DCE=1,2-dichloroethane

DCM=dichloromethane

DIEA=diisopropylethylamine

DMF=N,N-dimethylformamide

EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride

EtOAc=ethyl acetate

HBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

NMP=N-methylpyrrolidine

THF=tetrahydrofuran

LC-MS data was obtained using gradient elution on a parallel MUX™system, running four Waters 1525 binary HPLC pumps, equipped with aMux-UV 2488 multichannel UV-V is detector (recording at 215 and 254 nM)and a Leap Technologies HTS PAL Auto sampler using a Waters Xterra MSC18 4.6×50 mm column. A three minute gradient was run from 25% B (97.5%acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5%acetonitrile, 0.05% TFA) to 100% B. The system is interfaced with aWaters Micromass ZQ mass spectrometer using electrospray ionization. AllMS data was obtained in the positive mode unless otherwise noted. ¹H NMRdata was obtained on a Varian 400 MHz spectrometer.

General Procedure A: Preparation of Isothiocyanate

1,1′-thiocarbonylimidazole (1.1 mmol) was added to a solution of amine(1 mmol) in THF/DMF (2 mL, 1:1) and the reaction mixture was stirred at65-70° C. for 1 h. The product thus formed, was used for furthertransformation without isolation.

General Procedure B: Thiourea Formation and its Conversion toAminobenzimidazole

To a solution of an isothiocyanate (1 mmol) in THF/DMF (2 mL, 1:1) atroom temperature, a phenylene diamine (1 mmol) was added and thecontents were stirred at room temperature for 2 h. EDC (1.2 mmol) wasthen added to the reaction mixture and the contents were stirred at65-70° C. for 1 h. The reaction mixture was then cooled to roomtemperature, poured into ice-cold water (10 mL) and the solid wascollected by filtration. The crude product thus obtained was purified byflash column chromatography using DCM/methanol as eluent.

General Procedure C: Hydrolysis of Benzoate Ester

A solution of LiOH (12 mmol) in water (5 mL) was added to a solution ofester (3 mmol) in 1:1 THF/MeOH (10 mL) and the resulting mixture wasstirred at reflux for 6 h. The reaction mixture was cooled to roomtemperature and the organic solvents were removed in vacuo. The pH ofthe resulting suspension was adjusted by the dropwise addition of 10%aq. HCl to pH ˜6 and the precipitate thus formed was collected byfiltration, washed with water and dried under vacuum. The desiredcarboxylic acid thus obtained was used without further purification.

General Procedure D: Amide Formation Using a Coupling Agent

To a solution of carboxylic acid (1.0 mmol) in dry DMF or NMP (2.5 mL),HBTU (1.2 mmol) was added in one portion, the reaction mixture wasstirred at room temperature for ˜30 min. The reaction mixture was thenadded with the amine (1.1 mmol) and DIEA (1.5 mmol) and the resultingmixture was stirred at room temperature for 6-12 h or at 70-80° C. for1-3 h. The contents were diluted with ice-cold water (20 mL) and theproduct was precipitated. The pure product was either isolated afterfiltration with subsequent washings with water and ethyl acetate orthrough silica gel column chromatography using DCM/methanol as eluent.

General Procedure E: Amide Formation from Acid Chloride

Oxalyl chloride (10 mmol) was added to a suspension of a carboxylic acid(2 mmol) in dry DCM (4 mL) containing dry DMF (10 μL) and the mixturewas stirred at 50° C. for 6-12 h. The mixture was cooled to roomtemperature and the solvent was removed in vacuo to afford an acidchloride. Toluene (5 mL) was added to the acid chloride and the solventis removed to dryness in vacuo. This process was repeated to ensurecomplete removal of residual oxalyl chloride. The acid chloride thusobtained was dissolved in dry DCM (2 mL) and was added dropwise to asuspension of amine (2 mmol) in dry DCM (5 mL) containing pyridine (0.5mL) at 0° C. The mixture was allowed to warm to room temperature andstirred for 3-5 h. The organic volatiles were removed in vacuo, theprecipitate formed was suspended in water (20 mL) and collected byfiltration followed by water wash (20 mL). The amide thus obtained wasused without further purification.

General Procedure F: Reduction of Nitro to Amine

10% Pd/C (0.1 g) was added to a solution nitro compound (10 mmol) inTHF/MeOH (1:1, 50 mL). The resulting mixture was stirred at roomtemperature under a H₂ atmosphere for ˜12 h. The contents were thenfiltered through a pad of Celite and the solid washed with portions ofmethanol. The filtrate and the washings were combined and evaporated toafford the corresponding amine, which was not purified further and useddirectly in the next step.

General Procedure G: Ipso Substitution of o-Nitrohaloarene with Ammonia

To a suspension of an o-nitrohaloarene (10 mmol) in methanol (40 mL) wasadded concentrated aqueous NH₄OH (10 mL). The mixture was heated at50-60° C. for 4 h. The reaction mixture was concentrated in vacuo andthe precipitate formed was collected by filtration, washed with water(50 mL) and dried under vacuum to afford the correspondingo-nitroaniline, which was used for further transformation withoutfurther purification.

General Procedure H: Ipso Substitution of p-Nitrohaloarene with Amines

A mixture of a p-nitrohaloarene (5 mmol) and an amine (in excess) washeated as neat or in dioxane at 90° C. for 1-3 h. The volatiles wereremoved in vacuo and the resulting residue was suspended in ice-coldwater (50 mL) with stirring. The resulting precipitate was collected byfiltration, washed with water and dried under vacuum to provide thedesired product, which was used for further transformation withoutfurther purification.

Example 1 Synthesis of2-(Isoquinolin-3-ylamino)-1H-benzimidazole-5-carboxylic acidbenzothiazol-6-ylamide

3-Isothiocyanatoisoquinoline was prepared from 3-aminoisoquinoline (5mmol) as described in general procedure A.

The isothiocyanate from above was reacted with methyl3,4-diaminobenzoate (5 mmol) followed by cyclization using EDC asdescribed in general procedure B to obtain2-(Isoquinolin-3-ylamino)-1H-benzimidazole-5-carboxylic acid methylester. The ester was hydrolyzed to yield the corresponding carboxylicacid employing general procedure C.

Benzothiazol-6-ylamine (0.25 mmol) was coupled with aforementionedcarboxylic acid using HBTU employing general procedure D to provide2-(Isoquinolin-3-ylamino)-1H-benzimidazole-5-carboxylic acidbenzothiazol-6-ylamide. MS: m/z 437 (M+H)⁺.

Employing the procedure described for Example 1, the followingcompounds, shown in Table 2, were synthesized. TABLE 2

MS Ex. Ar R (m/z) 2 Isoquinolin-3-yl 1H-indazol-5-yl 420 3 Pyridin-2-yl1H-indazol-5-yl 370 4 Pyridin-2-yl 2-Methyl-benzooxazol-5-yl 385 5Pyridin-2-yl 1H-indazol-6-yl 370 6 Pyridin-3-yl 1H-indazol-6-yl 370 7Pyridin-2-yl benzothiazol-6-yl 387 8 Pyridin-2-yl 1H-benzotriazol-5-yl371 9 2,4-Dichlorophenyl 1-Methyl-1H-indazol-5-yl 452 102,4-Dichlorophenyl 1H-indazol-5-yl 437 11 Phenyl 1H-indol-5-yl 369 12Phenyl 1H-indazol-6-yl 369 13 Pyridin-4-yl 1H-indazol-6-yl 370 14Thiazol-2-yl 1H-indazol-6-yl 376 15 Phenyl 1H-benzotriazol-5-yl 370 16Pyridin-2-yl 1-Methyl-1H-indazol-5-yl 384 17 2-Chlorophenyl1H-indazol-6-yl 403 18 4,5-Dimethyl-thiazol-2-yl 1H-indazol-6-yl 404 192,4-Dichlorophenyl 1H-indazol-6-yl 437 20 Benzothiazol-2-yl1H-indazol-6-yl 426 21 4-phenylthiazol-2-yl 1H-indazol-6-yl 452 222-Fluorophenyl 1H-indazol-6-yl 387 23 2-Ethylphenyl 1H-indazol-6-yl 39724 2,4-Dichlorophenyl 1H-benzotriazol-5-yl 439

Example 25 Synthesis of2-(1-Isopropyl-1H-imidazol-2-ylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide

4-Amino-3-nitrobenzoic acid (27 mmol) was coupled with 6-aminoindazole(30 mmol) using HBTU (30 mmol) in dry DMF as the solvent employing thegeneral procedure D to afford4-amino-N-(1H-indazol-6-yl)-3-nitrobenzamide which was used for furthertransformation without further purification.

The nitroaniline from above was reduced to3,4-diamino-N-(1H-indazol-6-yl)-benzamide under hydrogen atmosphere asdescribed in the general procedure F.

2-Bromopropane (7 mmol) and K₂CO₃ (13 mmol) were added to a solution of2-nitroimidazole (4 mmol) in DMF (10 mL). The mixture was stirred at 60°C. for 4 h. The contents were cooled to room temperature and water (20mL) was added and the mixture was extracted with EtOAc (3×10 mL). Thecombined extracts were dried over MgSO₄, filtered and the solvent wasremoved in vacuo to afford 1-isopropyl-2-nitro-1H-imidazole. The productused for further transformation without further purification.

The nitroimidazole from above was reduced to1-isopropyl-2-amino-1H-imidazole under hydrogen atmosphere as describedin the general procedure F. The aminoimidazole (2 mmol) was convertedinto 1-isopropyl-2-isothiocyanato-1H-imidazole following the generalprocedure A.

The isothiocyanate (1 mmol) from above was reacted with3,4-diamino-N-(1H-indazol-6-yl)-benzamide (1 mmol) followed bycyclization using EDC as described in general procedure B to obtain2-(1-Isopropyl-1H-imidazol-2-ylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide. MS: m/z 401 (M+H)⁺.

Following the procedure in Example25,3,4-diamino-N-(1H-indazol-6-yl)-benzamide was utilized to synthesizethe compounds listed in Table 3. TABLE 3

Ex. Ar MS (m/z) 26 2,4-Dimethylphenyl 397 27 2-Isopropylphenyl 411 284-Chlorophenyl 403 29 Napthalen-1-yl 419 30 2-Tert-butylphenyl 425 31Biphenyl-2-yl 445 32 2-Propylphenyl 411 33 2,5-Dichlorophenyl 438 342-Methoxyphenyl 399 35 2-Trifluoromethylphenyl 437 363-Methylpyridin-2-yl 384 37 2-Trifluoromethoxyphenyl 453 383-Fluorophenyl 387 39 4-Fluorophenyl 387 40 3,5-Difluorophenyl 405 412-Butylphenyl 425 42 3-Ethyl-6-methylpyridin-2-yl 412 435-Chloro-2-methylphenyl 417 44 3-Fluoro-2-methylphenyl 411 455-Fluoro-2-methylphenyl 411 46 3-Chloro-2-methylphenyl 417 471-Cyclopentyl-1H-imidazol-2-yl 427

Example 48 Synthesis of2-(2-Isopropylphenylamino)-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

With rapid stirring, solid 2-chloro-4-fluorobenzoic acid (10 mmol) wasadded in portions in to a flask containing concentrated sulfuric acid (5mL). The reaction mixture was then cooled to 0° C. and 70% nitric acid(12 mmol) was added dropwise. After the addition was complete thereaction mixture was allowed to warm to room temperature and stirred for1-2 h. The reaction mixture was poured into 50 g of ice and the solidwas collected by filtration, washed with water and dried. The product,2-chloro-4-fluoro-5-nitrobenzoic acid, was used for furthertransformation without further purification.

2-chloro-4-fluoro-5-nitrobenzoic acid (5 mmol), obtained as above, wasconverted to the corresponding acid chloride, which was reacted with6-aminoindazole (5 mmol) following general procedure E. The product,2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide, thus obtained asa light orange solid, was used for further transformation withoutfurther purification. MS: m/z 335 (M+H)⁺.

Treatment of 2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide (4mmol), obtained as above, with ammonium hydroxide (4 mL) as described ingeneral procedure G gave4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide as a yellow solid.MS: m/z 332 (M+H)⁺.

Neat 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (3 mmol)obtained as above was heated with N-methylpiperazine (5 mL), followingthe general procedure H to afford4-amino-N-(1H-indazol-6-yl)-2-(4-methylpiperazin-1-yl)-5-nitrobenzamide.The product was reduced to4,5-diamino-N-(1H-indazol-6-yl)-2-(4-methylpiperazin-1-yl)benzamideunder hydrogenation conditions as described in the general procedure F.

The diamine (1 mmol) obtained from above was reacted with1-isopropyl-2-isothiocyanatobenzene (1 mmol) followed by cyclizationusing EDC as described in general procedure B to obtain2-(2-Isopropylphenylamino)-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)amide. MS: m/z 509 (M+H)⁺.

Following the procedure in Example 48,4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide was utilized tosynthesize the compounds listed in Table 4. TABLE 4

Ex. Ar X MS (m/z) 49 2-Isopropylphenyl Morpholin-4-yl 496 502-Trifluoromethylphenyl 4-Methylpiperazin-1-yl 535 51 3,5-Difluorophenyl4-Methylpiperazin-1-yl 503 52 2,4-Dichlorophenyl 4-Methylpiperazin-1-yl536 53 Thiazol-2-yl 4-Methylpiperazin-1-yl 474 542-Trifluoromethylphenyl Morpholin-4-yl 522 55 3,5-DifluorophenylMorpholin-4-yl 490 56 2,4-Dichlorophenyl Morpholin-4-yl 522 572-Trifluoromethylphenyl Piperidin-1-yl 520 58 3-Methylpyridin-2-yl4-Methylpiperazin-1-yl 482 59 Thiazol-2-yl Morpholin-4-yl 461 603-Methylpyridin-2-yl Morpholin-4-yl 469 61 1-Isopropyl-1H-imidazol-2-yl4-Methylpiperazin-1-yl 499 62 1-Cyclopentyl-1H-imidazol-2-yl4-Methylpiperazin-1-yl 525 63 1-Isopropyl-1H-imidazol-2-ylMorpholin-4-yl 486 64 1-Cyclopentyl-1H-imidazol-2-yl Morpholin-4-yl 51265 2-Ethyl-2H-pyrazol-3-yl Morpholin-4-yl 472

Example 66 Synthesis of2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid[3-(2-morpholin-4-yl-ethylamino)-1H-indazol-6-yl]-amide

To a solution of 2,6-dinitro-2H-indazole (1 mmol) (prepared by nitrationof 6-nitroindazole; Wrzeciono, et al., E. Pharmazie, 1980, 35, 593-596)in dry THF (4 mL) at 0° C., 2-morpholin-4-yl-ethylamine (2 mmol) wasadded dropwise. The reaction mixture was allowed to warm to roomtemperature and stirred for 12 h. The contents were diluted with ethylacetate (20 mL), washed with water (2×10 mL), and brine (10 mL) anddried over anhydrous sodium sulfate. The solvent was removed in vacuo toyield 3-(2-morpholin-4-yl-ethylamino)-6-nitro-1H-indazole as a brownsolid, which was reduced to3-(2-morpholin-4-yl-ethylamino)-1H-indazol-6-ylamine by hydrogenationfollowing general procedure F.

1-Isopropyl-2-isothiocyanatobenzene (5 mmol) and methyl3,4-diaminobenzoate (5 mmol) were reacted, following general procedureB, to yield 2-(2-Isopropylphenylamino)-1H-benzimidazole-5-carboxylicacid methyl ester, which was purified by silica gel chromatography usingDCM/ethyl acetate as eluent.

The ester obtained as above was hydrolyzed using general procedure C toyield 2-(2-isopropylphenylamino)-1H-benzimidazole-5-carboxylic acid. Thecarboxylic acid (0.25 mmol) was coupled with3-(2-morpholin-4-yl-ethylamino)-1H-indazol-6-ylamine (0.25 mmol) usingHBTU employing general procedure D. The product,2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid[3-(2-morpholin-4-yl-ethylamino)-1H-indazol-6-yl]-amide, was obtainedafter purification by silica gel chromatography using DCM/methanol aseluent. MS: m/z 539 (M+H)⁺.

Employing the procedure described for Example 66, the followingcompounds, shown in Table 5, were synthesized. TABLE 5

Ex. R MS (m/z) 67 3-Morpholin-4-yl-propylamino 553 68 Methylamino 440

Example 69 Synthesis of2-(pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid(3-amino-1H-indazol-6-yl)-amide

To a solution of 2-fluoro-4-nitrobenzonitrile (10 mmol) in isopropanol(30 mL) was added aqueous hydrazine (4 mL). The resulting solution washeated at 80° C. for 12 h. The reaction mixture was then concentrated,water (30 mL) was added, and the solution was extracted with ethylacetate (2×25 mL). The combined organics were washed with water (30 mL)and brine (30 mL) and dried over anhydrous sodium sulfate. The volatileswere removed in vacuo yielding 3-amino-6-nitroindazole as an orangesolid, which was utilized for further transformation without furtherpurification.

The nitro compound from above was hydrogenated, following generalprocedure F, to yield 3,6-diaminoindazole.

2-Isothiocyanatopyridine (4 mmol), prepared from 2-aminopyridineemploying general procedure A, was reacted with methyl3,4-diaminobenzoate as described in general procedure B to afford2-(pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid methyl ester.This ester was hydrolyzed, following general procedure C, to obtain2-(pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid.

The carboxylic acid (0.5 mmol) from above was coupled withaforementioned 3,6-diaminoindazole (0.5 mmol) using HBTU as described ingeneral procedure D to afford2-(pyridin-2-ylamino)-1H-benzimidazole-5-carboxylic acid(3-amino-1H-indazol-6-yl)-amide. MS: m/z 385 (M+H)⁺.

Example 70 Synthesis of2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid{3-[(1-methylpiperidine-4-carbonyl)-amino]-1H-indazol-6-yl}-amide

1-Methylpiperidine-4-carbonyl chloride (1 mmol), prepared from itscorresponding carboxylic acid using general procedure E, was reactedwith 3,6-diaminoindazole (1 mmol) (see Example 69) employing generalprocedure E to yield 1-methylpiperidine-4-carboxylic acid(6-amino-1H-indazol-3-yl)-amide.

2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (0.3 mmol;see Example 66) was coupled with aforementioned1-methylpiperidine-4-carboxylic acid (6-amino-1H-indazol-3-yl)-amide(0.3 mmol) using HBTU as described in general procedure D to afford thedesired product,2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid{3-[(1-methylpiperidine-4-carbonyl)-amino]-1H-indazol-6-yl}-amide. MS:m/z 551 (M+H)⁺.

Employing the procedure described for Example 70, the followingcompounds, shown in Table 6, were synthesized. TABLE 6

Ex. Ar R MS (m/z) 71 Pyridin-2-yl Methyl 427 72 2,4-DichlorophenylMethyl 494 73 2,4-Dichlorophenyl Phenyl 556

Example 74 Synthesis of2-(2-isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid(3-methoxy-1H-indazol-6-yl)-amide

To a solution of 2,6-dinitro-2H-indazole(1 mmol) (prepared by nitrationof 6-nitroindazole; Wrzeciono, et al., E. Pharmazie, 1980, 35, 593-596)in dry THF (4 mL) at 0° C., solid sodium methoxide (4 mmol) was added inportions. The reaction mixture was allowed to warm to room temperatureand stirred for 12 h. The contents were diluted with ethyl acetate (20mL), washed with water (2×10 mL) and brine (10 mL) and dried overanhydrous sodium sulfate. The solvent was removed in vacuo to yield3-methoxy-6-nitro-1H-indazole as a brown solid, which was reduced to3-methoxy-1H-indazol-6-ylamine by hydrogenation following generalprocedure F.

2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (0.3 mmol;see Example 66) was coupled with aforementioned3-methoxy-1H-indazol-6-ylamine (0.3 mmol) using HBTU as described ingeneral procedure D to afford the desired product,2-(2-isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid(3-methoxy-1H-indazol-6-yl)-amide. MS: m/z 441 (M+H)⁺.

Example 75 Synthesis of 2-(2isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid[3-(2-morpholin-4-ylethoxy)-1H-indazol-6-yl]-amide

To a solution of 2-morpholin-4-yl-ethanol (3 mmol) in dry THF (6 mL)sodium hydride (4 mmol; 60% dispersion in oil) was added at 0° C. inportions. The alkoxide thus formed, was reacted with2,6-dinitro-2H-indazole(1 mmol) as described in Example 74 to yield3-(2-morpholin-4-ylethoxy)-6-nitro-1H-indazole as a brown solid whichwas reduced to 3-(2-morpholin-4-ylethoxy)-1H-indazol-6-ylamine byhydrogenation following general procedure F.

2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid (0.3 mmol;see Example 66) was coupled with aforementioned3-(2-morpholin-4-ylethoxy)-1H-indazol-6-ylamine (0.3 mmol) using HBTU asdescribed in general procedure D to afford the desired product, 2-(2isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid[3-(2-morpholin-4-ylethoxy)-1H-indazol-6-yl]-amide. MS: m/z 540 (M+H)⁺.

Example 76 Synthesis of2-(2,4-dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid(3-morpholin-4-ylmethyl-1H-indazol-6-yl)-amide

To a solution of 6-nitro-1H-indazole-3-carbaldehyde (0.5 mmol; preparedfrom 6-nitroindole; Zhang et al., J. Med. Chem. 2001, 44, 1021-1024) indry THF (1 mL), morpholine (1 mmol) and acetic acid (2 drops) were addedat room temperature and the mixture was stirred for 1 h. The reactionmixture was treated with solid NaCNBH₃ (2 mmol) with stirring continuedfor additional 4 h. The contents were poured into water and extractedwith ethyl acetate (2×10 mL). The combined organics were washed withsaturated aqueous NaHCO₃ (10 mL) and brine (10 mL) and dried overanhydrous sodium sulfate. Removal of the solvent in vacuo afforded thedesired product, 3-(morpholin-4-yl)methyl-6-nitro-1H-indazole.

Hydrogenation of the aforementioned nitro compound, following thegeneral procedure F gave 3-(morpholin-4-y)lmethyl-1H-indazol-6-ylamine.

2,4-Dichloro-1-isothiocyanatobenzene (5 mmol) and methyl3,4-diaminobenzoate (5 mmol) were reacted, following general procedureB, to yield 2-(2,4-dichlorophenylamino)-3H-benzimidazole-5-carboxylicacid methyl ester, which was purified by silica gel chromatography usingDCM/ethyl acetate as eluent.

The ester obtained as above was hydrolyzed using general procedure C toyield 2-(2,4-dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid.The carboxylic acid (0.25 mmol) was coupled with3-(morpholin-4-y)lmethyl-1H-indazol-6-ylamine (0.25 mmol) using HBTUemploying general procedure D. The product,2-(2,4-dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid(3-morpholin-4-ylmethyl-1H-indazol-6-yl)-amide, was obtained as a lightbrown solid after purification by silica gel chromatography usingDCM/methanol as eluent. MS: m/z 536 (M+H)⁺.

Example 77 Synthesis of2-(2,4-dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid(3-methyl-1H-indazol-6-yl)-amide

To a solution of 6-nitro-1H-indazole-3-carbaldehyde (0.5 mmol; preparedfrom 6-nitroindole; Zhang et al., J. Med. Chem. 2001, 44, 1021-1024) inethanol (2 mL), solid KOH (5 mmol) and aqueous hydrazine (0.5 mL) wereadded and the contents were irradiated under microwave conditions at 80°C. for 10 min. The reaction mixture was neutralized with acetic acid topH ˜7, concentrated in vacuo, diluted with water and extracted withethyl acetate (3×8 mL). The combined organics were washed with saturatedaqueous NaHCO₃ (10 mL) and brine (10 mL) and dried over anhydrous sodiumsulfate. Removal of the solvent in vacuo afforded the desired product,3-methyl-1H-indazol-6-ylamine.

The amine (0.25 mmol), obtained as above, was coupled with2-(2,4-dichloro-phenylamino)-3H-benzimidazole-5-carboxylic acid (0.25mmol; see Example 76) using HBTU employing general procedure D. Theproduct, 2-(2,4-dichlorophenylamino)-3H-benzimidazole-5-carboxylic acid(3-methyl-1H-indazol-6-yl)-amide, was obtained as a light brown solidafter purification by silica gel chromatography using DCM/methanol aseluent. MS: m/z 452 (M+H)⁺.

Example 78 Synthesis of2-(2-ethylphenylamino)-3H-benzimidazole-5-carboxylic acid(3-chloro-1H-indazol-6-yl)-amide

To a solution of 6-nitroindazole (2 mmol) in DCE (5 mL), sulfurylchloride (10 mmol) was added and the resulting mixture was heated 80° C.for 3-5 h. The reaction mixture was concentrated, added with 5% aqueousNa₂CO₃ solution (20 mL) and extracted with EtOAc (2×15 mL). The combinedorganics were then washed with water (20 mL) and brine (20 mL) and driedover anhydrous Na₂SO₄. Removal of volatiles afforded3-chloro-6-nitro-1H-indazole as a yellow solid.

To a solution of nitro compound (0.5 mmol) from above in methanol (2mL), was added solid sodium hydrosulfite (3 mmol) and concentratedammonium hydroxide (0.25 mL). The resulting mixture was stirred at roomtemperature for 12 h. The contents were filtered through Celite and thesolvent was removed in vacuo. The residue obtained was purified bysilica gel chromatography using ethyl acetate/hexane as eluant to yield3-chloro-1H-indazol-6-ylamine as a light brown solid.

2-Ethyl-1-isothiocyanatobenzene (3 mmol) and methyl 3,4-diaminobenzoate(3 mmol) were reacted, following general procedure B, to yield2-(2-ethylphenylamino)-3H-benzimidazole-5-carboxylic acid methyl ester,which was purified by silica gel chromatography using DCM/ethyl acetateas eluent.

The ester obtained as above was hydrolyzed using general procedure C toyield 2-(2-ethylphenylamino)-3H-benzimidazole-5-carboxylic acid. Thecarboxylic acid (0.25 mmol) was coupled with3-(morpholin-4-y)lmethyl-1H-indazol-6-ylamine (0.25 mmol) using HBTUemploying general procedure D. The product,2-(2-ethylphenylamino)-3H-benzimidazole-5-carboxylic acid(3-chloro-1H-indazol-6-yl)-amide, was obtained as a light brown solidafter purification by silica gel chromatography using DCM/methanol aseluent. MS: m/z 431 (M+H)⁺.

Example 79 Synthesis of2-[6-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester

To a solution of 1-Boc-4-piperidone (5 mmol) in dry THF (20 mL) wasadded solid Ba₂CO₃ (10 mmol). The resulting mixture was stirredvigorously. The reaction mixture was treated with pyrrolidonehydrotribromide (5.5 mmol) in portions at room temperature. After 3h,the contents were filtered and the solvent removed. The crude reactionmixture containing the product, 3-bromo-4-oxo-piperidine-1-carboxylicacid tert-butyl ester, was used for further transformation withoutfurther purification.

To a solution of the bromo compound (5 mmol), obtained as above, inacetone (20 mL) was added solid thiourea (6 mmol) and solid K₂CO₃ (10mmol), and the reaction mixture was stirred at room temperature for 12h. To the reaction mixture was added BOC anhydride (5 mmol), and thereaction was stirred for 4 h. The contents were then filtered, and thesolvent was removed. The residue obtained was purified by silica gelchromatography using DCM/methanol as eluent. The product,2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acidtert-butyl ester, was obtained a light yellow solid.

The amine (0.5 mmol) from above was converted to correspondingisothiocyanate using general procedure A, which was then reacted with3,4-diamino-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 25)according to general procedure B to yield2-[6-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester. MS: m/z 531 (M+H)⁺.

Example 80 Synthesis of2-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-ylamino)-3H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

To a solution of2-[6-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester (0.25 mmol; see Example 79) in methanol (1 mL), 4MHCl in dioxane (0.5 mL) was added. The resulting mixture was stirred atroom temperature for 5-6 h. The volatiles were removed in vacuo, theresidue obtained was suspended in ether. The solid obtained wascollected by filtration, washed with ether and dried in vacuo to afford2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamino)-3H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 431(M+H)⁺.

Example 81 Synthesis of2-(2-isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid[1-(2-hydroxy-ethyl)-1H-indazol-5-yl]-amide

To a solution of 2-chloro-5-nitrobenzaldehyde (4 mmol) in ethanol (10mL) was added aqueous hydrazine (5 mmol), and the resulting solution washeated at reflux for 2 h to complete hydrazone formation. DIEA (10 mmol)was added to the reaction mixture, and the reaction was subjected tomicrowave irradiation at 150° C. for 8-10 h. After removal of volatilesin vacuo, the residue obtained was dissolved in EtOAc (30 mL), washedwith water (20 mL) and brine (20 mL) and dried over anhydrous sodiumsulfate. The solvent was removed in vacuo to yield the product,2-(5-nitroindazol-1-yl)-ethanol.

The nitro compound from above was reduced under hydrogenation conditionsas described in general procedure F to afford2-(5-aminoindazol-1-yl)-ethanol. The aminoindazole (0.3 mmol) wascoupled with 2-(2-Isopropylphenylamino)-1H-benzimidazole-5-carboxylicacid (0.3 mmol; see Example 66) using HBTU as described in generalprocedure D to provide of2-(2-isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid[1-(2-hydroxy-ethyl)-1H-indazol-5-yl]-amide. MS: m/z 455 (M+H)⁺.

Example 82 Synthesis of2-(2-cyclohexylphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide

To a solution of 1-bromo-2-cyclohexyl-benzene (5 mmol) in dioxane (20mL) was added solid Pd(OAc)₂ (0.1 g) and solid CsCO₃ (10 mmol).tert-Butyl carbamate (7 mmol) was added to the reaction mixture, and thecontents were heated at 80° C. for 2 h. The reaction mixture was cooledto room temperature and filtered through Celite. The solvent was removedin vacuo and the residue obtained was purified by flash columnchromatography using DCM as eluant to yield(2-cyclohexylphenyl)-carbamic acid tert-butyl ester.

The carbamate obtained as above was treated with 4 M HCl in dioxanefollowing the procedure described in Example 80 to afford2-cyclohexylphenylamine as a hydrochloride salt.

To a solution of aforementioned amine hydrochloride (1 mmol) in dry DMF(2 mL) was added DIEA (1.5 mmol) and 1,1′-thiocarbonylimidazole (1mmol). The reaction mixture was heated at 70° C. for 1 h to provide1-cyclohexyl-2-isothiocyanatobenzene as described in general procedureA.

The isothiocyanate (0.5 mmol) was reacted with3,4-diamino-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 25)according to general procedure B to yield2-(2-cyclohexylphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide. MS: m/z 451 (M+H)⁺.

Example 83 Synthesis of2-(3-methylthiophen-2-ylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide

To a solution of 3-methylthiophene-2-carboxylic acid (7 mmol) inanhydrous dioxane (20 mL) was added diphenyl phosphoryl azide (7 mmol),tert-butanol (6 mL) and TEA (1 mL). The resulting mixture was stirred atreflux for 16 h. The reaction mixture was cooled to room temperature,diluted with H₂O (40 mL), and was extracted with EtOAc (3×20 mL). Thecombined extracts were dried (MgSO₄) and the solvent was removed invacuo. The residue obtained was purified by flash column chromatographyusing hexanes/EtOAc (7:3) as eluent to afford(3-methylthiophen-2-yl)-carbamic acid tert-butyl ester.

To a solution of carbamate (3 mmol), obtained as above, in dry DCM (10mL) was added with 4M HCl in dioxane (8 mL). The mixture was stirred atroom temperature for 2 h. The solvent was removed in vacuo. The solidobtained washed with anhydrous Et₂O (3×10 mL) and dried under reducedpressure to afford 3-methylthiophen-2-ylamine as hydrochloride salt.

To a solution of aforementioned amine hydrochloride (1 mmol) in dry DMF(2 mL) was added DIEA (1.5 mmol) and 1,1′-thiocarbonylimidazole (1mmol). The reaction mixture was heated at 70° C. for 1 h to provide1-cyclohexyl-2-isothiocyanatobenzene as described in general procedureA.

The isothiocyanate (0.5 mmol) was reacted with3,4-diamino-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 25)according to general procedure B to yield2-(2-cyclohexylphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide. MS: m/z 389 (M+H)⁺.

Example 84 Synthesis of 1H-indazole-6-carboxylic acid[2-(2-isopropylphenylamino)-3H-benzimidazol-5-yl]-amide

To a solution of 2-chloro-5-nitro-1H-benzimidazole (1.5 mmol; preparedfrom nitration of 2-chloro-1H-benzimidazole; Galy et al., J. Heterocycl.Chem. 1997, 34, 6, 1781-1788) in dry NMP (3 mL) was added2-isopropylaniline (4 mmol). The resulting solution was subjected tomicrowave irradiation at 150° C. for 1 h. The contents were cooled toroom temperature, diluted with water (20 mL) and extracted with EtOAc(2×15 mL). The combined extracts were then washed with water (20 mL) andbrine (20 mL) and dried over anhydrous sodium sulfate. The solvent wasremoved in vacuo and the residue obtained was purified by silica gelchromatography using EtOAc/hexane as eluent to obtain(2-isopropylphenyl)-(5-nitro-1H-benzimidazol-2-yl)-amine as light yellowsolid.

The nitro compound (1 mmol) as above was reduced under hydrogenationconditions as described in general procedure F to affordN²-(2-isopropylphenyl)-1H-benzimidazole-2,5-diamine.

Methyl Indazole-6-carboxylate (4 mmol; Batt et al., J. Med. Chem. 2000,43, 41-58) was hydrolyzed as in general procedure C to obtain1H-Indazole-6-carboxylic acid. The carboxylic acid (0.5 mmol) wascoupled with aforementionedN²-(2-isopropylphenyl)-1H-benzimidazole-2,5-diamine (0.5 mmol) usingHBTU as described in general procedure D to yield1H-indazole-6-carboxylic acid[2-(2-isopropylphenylamino)-3H-benzimidazol-5-yl]-amide as an off-whitesolid. MS: m/z 411 (M+H)⁺.

Example 85 Synthesis of6-(4-methylpiperazin-1-yl)-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-5-yl)-amide

2-Chloro-4-fluoro-N-(1H-indazol-5-yl)-5-nitrobenzamide was obtained from2-chloro-4-fluoro-5-nitrobenzoic acid (5 mmol) and 5-aminoindazole (5mmol) following the procedure described in Example 48. The product,obtained as a yellow solid, was used for further transformation withoutfurther purification. MS: m/z 335 (M+H)⁺.

Treatment of 2-Chloro-4-fluoro-N-(1H-indazol-5-yl)-5-nitrobenzamide (4mmol), obtained as above, with ammonium hydroxide (4 mL) as described ingeneral procedure G gave4-amino-2-chloro-N-(1H-indazol-5-yl)-5-nitrobenzamide as a yellow solid.MS: m/z 332 (M+H)⁺.

4-amino-2-chloro-N-(1H-indazol-5-yl)-5-nitrobenzamide (3 mmol) fromabove was reacted N-methylpiperazine (5 mL), following the procedure inExample 48. The product formed was reduced to4,5-diamino-N-(1H-indazol-5-yl)-2-(4-methylpiperazin-1-yl)benzamideunder hydrogenation conditions as described in the general procedure F.

The diamine (1 mmol) obtained from above was reacted with1-trifluoromethyl-2-isothiocyanatobenzene (1 mmol) followed bycyclization using EDC as described in general procedure B to obtain2-(2-trifluoromethylphenylamino)-6-(4-methylpiperazin1-yl)-1H-benzimidazole-5-carboxylic acid (1H-indazol-5-yl)amide. MS: m/z535 (M+H)⁺.

Example 86 Synthesis of6-morpholin-4-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-5-yl)-amide

4-Amino-2-chloro-N-(1H-indazol-5-yl)-5-nitrobenzamide (3 mmol; seeExample 85) was reacted morpholine (5 mL), following the procedure G.The product formed was reduced to4,5-diamino-N-(1H-indazol-5-yl)-2-morpholin-4-yl-benzamide underhydrogenation conditions as described in the general procedure F.

The diamine (1 mmol) obtained from above was reacted with1-trifluoromethyl-2-isothiocyanatobenzene (1 mmol) followed bycyclization using EDC as described in general procedure B to obtain6-morpholin-4-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-5-yl)-amide. MS: m/z 522 (M+H)⁺.

Example 87 Synthesis of4-[6-(1H-indazol-6-ylcarbamoyl)-2-(2-trifluoromethylphenylamino)-3H-benzimidazol-5-yl]-piperazine-1-carboxylicacid tert-butyl ester

4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (3 mmol; seeExample 48) in dioxane (5 mL) was reacted with piperazine (9 mmol)following the general procedure H to afford4-amino-N-(1H-indazol-6-yl)-5-nitro-2-piperazin-1-yl-benzamide. Theproduct was dissolved in dry THF (6 mL) and was treated with BOCanhydride (3.6 mmol) and stirred for 4-6 h. The solvent was removed todryness, and the residue obtained was suspended in ether (50 mL) withstirring. The solid formed was collected by filtration, washed withether and dried in vacuo to afford4-[5-amino-2-(1H-indazol-6-ylcarbamoyl)-4-nitro-phenyl]-piperazine-1-carboxylicacid tert-butyl ester.

To a solution of nitro compound (1 mmol) from above in methanol (4 mL)was added solid sodium hydrosulfite (4 mmol) and concentrated ammoniumhydroxide (0.5 mL). The resulting mixture was heated at reflux for 5-8h. The reaction was concentrated, and the residue was taken up in THF(20 mL) with vigorous stirring. The contents were then filtered throughCelite and the solvent was removed in vacuo to provide4-[4,5-diamino-2-(1H-indazol-6-ylcarbamoyl)-phenyl]piperazine-1-carboxylicacid tert-butyl ester which was used for further transformation withoutfurther purification.

The diamine (0.3 mmol) from above was reacted with1-trifluoromethyl-2-isothiocyanatobenzene (0.3 mmol) followed bycyclization using EDC as described in general procedure B to obtain4-[6-(1H-indazol-6-ylcarbamoyl)-2-(2-trifluoromethylphenylamino)-3H-benzimidazol-5-yl]-piperazine-1-carboxylicacid tert-butyl ester. MS: m/z 621 (M+H)⁺.

Example 88 Synthesis of6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

The product from Example 87 was treated with 4M HCl in dioxane employingthe procedure described for Example 80 to afford of6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 521(M+H)⁺.

Example 89 Synthesis of4-[6-(1H-indazol-6-ylcarbamoyl)-2-(3-methylpyridin-2-ylamino)-3H-benzimidazol-5-yl]-piperazine-1-carboxylicacid tert-butyl ester

4-[4,5-Diamino-2-(1H-indazol-6-ylcarbamoyl)-phenyl]piperazine-1-carboxylicacid tert-butyl ester (see Example 87) was reacted with2-isothiocyanato-3-methylpyridine (0.3 mmol; prepared from3-methylpyridin-2-ylamine following general procedure A) followed bycyclization using EDC as described in general procedure B to obtain4-[6-(1H-indazol-6-ylcarbamoyl)-2-(3-methylpyridin-2-ylamino)-3H-benzimidazol-5-yl]-piperazine-1-carboxylicacid tert-butyl ester. MS: m/z 568 (M+H)⁺.

Example 90 Synthesis of2-(3-methylpyridin-2-ylamino)-6-piperazin-1-yl-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

The product from Example 89 was treated with 4M HCl in dioxane employingthe procedure described for Example 80 to afford of2-(3-methylpyridin-2-ylamino)-6-piperazin-1-yl-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 468(M+H)⁺.

Example 91 Synthesis2-(2,6-diethylphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide

A solution of 1,3-diethyl-2-isothiocyanatobenzene (0.5 mmol) in 1:1DMF/THF (2 mL) was reacted with3,4-diamino-N-(1H-indazol-6-yl)-benzamide (0.5 mmol; see Example 25)according to general procedure B to yield2-(2,6-diethylphenylamino)-3H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide. MS: m/z 425 (M+H)⁺.

Example 92 Synthesis6-diisobutylamino-2-(2-trifluoromethylphenylamino)-3H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1mmol; see Example 48) in NMP (2 mL) was added with diisobutylamine (0.5mL), and the resulting mixture was subjected to microwave irradiation at140° C. for 1 h. The reaction mixture was cooled to room temperature,diluted with water (20 mL). The solid formed was collected byfiltration, washed with water, and dried in vacuo to provide4-amino-2-diisobutylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.

The nitro compound (0.5 mmol) as above was reduced under hydrogenationconditions as described in general procedure F to afford4,5-diamino-2-diisobutylamino-N-(1H-indazol-6-yl)benzamide.

The diamine (0.3 mmol) from above was reacted with1-trifluoromethyl-2-isothiocyanatobenzene (0.3 mmol) followed bycyclization using EDC as described in general procedure B to obtain6-diisobutylamino-2-(2-trifluoromethylphenylamino)-3H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide. MS: m/z 564 (M+H)⁺.

Example 93 Synthesis of6-diethylamino-2-(3-methylpyridin-2-ylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1mmol; see Example 48) in NMP (2 mL) was added with diethylamine (1.0mL), and the resulting mixture was subjected to microwave irradiation at70° C. for 1 h. The reaction mixture was cooled to room temperature,diluted with water (20 mL). The solid formed was collected byfiltration, washed with water, and dried in vacuo to provide4-amino-2-diethylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.

The nitro compound (0.5 mmol) as above was reduced under hydrogenationconditions as described in general procedure F to afford4,5-diamino-2-diethylamino-N-(1H-indazol-6-yl)benzamide.

The diamine (0.3 mmol) from above was reacted with2-isothiocyanato-3-methylpyridine (0.3 mmol; prepared from3-methylpyridin-2-ylamine following general procedure A) followed bycyclization using EDC as described in general procedure B to obtain6-diethylamino-2-(3-methyl-pyridin-2-ylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide. MS: m/z 455 (M+H)⁺.

Following the procedure in Example 93,4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide was utilized tosynthesize the compounds listed in Table 7. TABLE 7

MS Ex. Ar X (m/z) 94 2-Trifluoromethylphenyl 2,6-Dimethylmorpholin-4-yl550 95 2-Trifluoromethylphenyl Diethylamino 508 962-Trifluoromethylphenyl (2-dimethylaminoethyl) 537 methylamino 972-Trifluoromethylphenyl 4-Dimethylaminopiperidin-1-yl 563 982-Trifluoromethylphenyl Dipropylamino 536 99 3-Methylpyridin-2-ylDipropylamino 483 100 2-Trifluoromethylphenyl Bis-(2-methoxyethyl)amino568 101 2-Trifluoromethylphenyl 4-Hydroxypiperidin-1-yl 536 1022-Trifluoromethylphenyl Ethyl-(2-methoxyethyl)amino 538 1033-Methylpyridin-2-yl Bis-(2-methoxyethyl)amino 515 1043-Methylpyridin-2-yl pyrrolidin-1-yl 453 105 2-Trifluoromethylphenylpyrrolidin-1-yl 506 106 2-Trifluoromethylphenyl (2-Dimethylaminoethyl)551 ethylamino 107 3 -Methylpyridin-2-yl 4-Hydroxypiperidin-1-yl 483 1083 -Methylpyridin-2-yl Ethyl-(2-methoxyethyl)amino 485 1092-Trifluoromethylphenyl Ethylpropylamino 522 110 3-Methylpyridin-2-ylEthylpropylamino 469 111 2-Trifluoromethylphenyl4-Isopropylpiperazin-1-yl 563 112 2-TrifluoromethylphenylEthylmethylamino 494 113 3-Methylpyridin-2-yl Ethylmethylamino 441 1143-Methylpyridin-2-yl 4-Isopropylpiperazin-1-yl 510

Example 115 Synthesis of2-(3-Chloropyridin-2-ylamino)-6-diethylamino-1H-benzoimidazole-5-carboxylicacid(1H-indazol-6-yl)-amide

To a suspension of 2-chloro-4-fluoro-5-nitrobenzoic acid (5 mmol),oxalyl chloride (15 mmol) was added in dry DCM (5 mL) containing dry DMF(0.2 mL), and the mixture was stirred at 50° C. After the reaction wascomplete (˜60 min), the solvent was removed in vacuo to afford acidchloride. Toluene (˜1 mL) was added to the acid chloride, and thesolvent was removed to dryness in vacuo to ensure complete removal ofresidual oxalyl chloride. The product, 4-chloro-2-fluoro-5-nitrobenzoylchloride, was obtained as a light yellow solid.

The acid chloride (˜5 mmol) obtained as above was dissolved in EtOAc (5mL) and was added dropwise to a suspension of 6-aminoindazole (4.5 mmol)in EtOAc (15 mL) containing triethylamine (1 mL) at 0-5° C. The mixturewas then allowed to warm to room temperature and stirred for 2-3 h. Mostof the solvent was removed in vacuo and the residue was added withhexane. The solids were collected on a filter, washed twice withhexane/EtOAc (5:1) and thrice with water. The residue was dried in vacuoto afford the product,2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide, as a yellowsolid, which was used for further transformation without furtherpurification. MS: m/z 335 (M+H)⁺.

To a solution of 2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide(3 mmol) in dioxane (6 mL) was added concentrated aqueous NH₄OH (3 mL).The resulting mixture was heated at 60° C. for 2-3 h. The completedreaction afforded the product,2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide. To the crudereaction mixture was added diethylamine (45 mmol). The mixture thenheated at 60° C. for 6 h. After the reaction was complete, the volatileswere removed in vacuo, and the residue was suspended in cold water. Thesolid was collected by filtration, washed with water, and dried in vacuoto provide 4-amino-2-diethylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.

The nitro compound (2 mmol) obtained as above was reduced underhydrogenation conditions as described in general procedure F to afford4,5-diamino-2-diethylamino-N-(1H-indazol-6-yl)benzamide.

To a stirred solution of 2-amino-3-chloropyridine (2 mmol) in CHCl₃ (5mL) was added 0.7 M aqueous sodium bicarbonate solution at 0° C.Thiophosgene (2.2 mmol) was added dropwise at 0° C., and the contentswere allowed to warm to RT gradually over a period of 2 h. The reactionmixture was diluted with DCM (20 mL), and the layers were separated. Theorganic layer washed with water (2×10 mL), followed with brine (10 mL)and dried over anhydrous Na₂SO₄. The volatiles were removed in vacuo,and the product, 3-chloro-2-isothiocyanatopyridine, was used without anypurification.

The diamine (0.3 mmol) from above was reacted with3-chloro-2-isothiocyanatopyridine (0.3 mmol) followed by cyclization insitu using EDC as described in general procedure B to obtain2-(3-chloropyridin-2-ylamino)-6-diethylamino-1H-benzoimidazole-5-carboxylicacid(1H-indazol-6-yl)-amide. MS: m/z 475 (M+H)⁺.

Following the procedure in Example 115,4,5-diamino-2-diethylamino-N-(1H-indazol-6-yl)benzamide was utilized tosynthesize the compounds listed in Table 8. TABLE 8

MS Ex. Ar (m/z) 116 3-Trifluoromethylpyridin-2-yl 509 1171-Cyclopentyl-1H-imidazol-2-yl 498 118 Cyclohexyl 446 119 Cyclopentyl432 120 Bicyclo[2.2.1]hept-2-yl 458 121 Isopropyl 406 1223-Ethyl-6-methylpyridin-2-yl 483 123 2,5-Difluorophenyl 476 1243,5-Difluorophenyl 476 125 2-Chloro-5-trifluoromethylphenyl 542 1262-Trifluoromethoxyphenyl 524 127 3-Methoxycarbonylphenyl 498 1282-Isopropylphenyl 482 129 4-Chlorophenyl 474 130 2,4-Dichlorophenyl 508131 2,6-Difluorophenyl 476 132 2-Methoxyphenyl 470

Example 133 Synthesis of 6-diethylamino-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acid benzothiazol-6-ylamide

6-aminobenzothioazole (4.5 mmol) was reacted with4-chloro-2-fluoro-5-nitrobenzoyl chloride (5 mmol) employing theconditions described in Example 115. The reaction mixture was dilutedwith EtOAc (40 mL) and washed with water (2×40 mL) and brine (40 mL) anddried over anhydrous Na₂SO₄. Removal of organics afforded the product,N-benzothiazol-6-yl-2-chloro-4-fluoro-5-nitrobenzamide as a yellowsolid. MS: m/z 352 (M+H)⁺.

A solution of the aforementioned amide (3 mmol) in dioxane was reactedwith aqueous NH₄OH and subsequently with diethylamine using the one-potprocedure described for Example 115 to yield4-amino-N-benzothiazol-6-yl-2-diethylamino-5-nitrobenzamide as a yellowsolid.

The nitro compound (2 mmol) obtained as above was reduced underhydrogenation conditions as described in general procedure F to afford4,5-diamino-N-benzothiazol-6-yl-2-diethylaminobenzamide.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toobtain6-diethylamino-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid benzothiazol-6-ylamide. MS: m/z 525 (M+H)⁺.

Following the procedure in Example 133,4,5-diamino-N-benzothiazol-6-yl-2-diethylaminobenzamide was utilized tosynthesize the compounds listed in Table 9. TABLE 9

MS Ex. Ar (m/z) 134 Bicyclo[2.2.1]hept-2-yl 475 135 Isopropyl 423 1362,5-Difluorophenyl 493 137 3,5-Difluorophenyl 493 138 2,4-Dichlorophenyl526 139 2-Trifluoromethoxyphenyl 541 140 2-Isopropylphenyl 499

Example 141 Synthesis of6-(4-methyl-piperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid benzothiazol-6-ylamide

A solution of N-benzothiazol-6-yl-2-chloro-4-fluoro-5-nitrobenzamide (2mmol) in dioxane (4 mL) was reacted with aqueous NH₄OH using theconditions described in Example 115. After the formation of4-amino-N-benzothiazol-6-yl-2-chloro-5-nitrobenzamide was complete, thereaction mixture was charged with N-methylpiperazine (12 mmol). Thecontents were heated at reflux for 10 h, and the reaction mixture wascooled to RT. The contents were poured onto ice cold water with vigorousstirring. The solid formed was collected by filtration, washed withwater, and dried in vacuo to provide the product,4-amino-N-benzothiazol-6-yl-2-(4-methyl-piperazin-1-yl)-5-nitrobenzamideas a yellow solid.

The nitro compound (2 mmol) obtained as above, was reduced underhydrogenation conditions as described in general procedure F to afford4,5-Diamino-N-benzothiazol-6-yl-2-(4-methyl-piperazin-1-yl)-benzamide.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toobtain6-(4-methyl-piperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid benzothiazol-6-ylamide. MS: m/z 552 (M+H)⁺.

Following the procedure in Example 141,4-amino-N-benzothiazol-6-yl-2-chloro-5-nitrobenzamide was utilized tosynthesize the compounds listed in Table 10. TABLE 10

Ex. Ar R MS (m/z) 142 3-Methylpyridin-2-yl 4-methylpiperazin-1-yl 499143 2-Trifluoromethylphenyl Morpholino-4-yl 539 144 3-Methylpyridin-2-ylMorpholino-4-yl 486

Example 145 Synthesis of6-(3,5-dimethylpiperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

A solution of 2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1mmol) in dioxane (2 mL) was reacted with aqueous NH₄OH using theconditions described in Example 115. After the formation of2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide was complete, thereaction mixture was charged with 2,6-dimethylpiperazine (6 mmol). Thecontents were heated at reflux for 10 h, and the reaction mixture wascooled to RT. The contents were poured onto ice cold water with vigorousstirring. The solid formed was collected by filtration, washed withwater, and dried in vacuo to provide the product,4-amino-2-(3,5-dimethyl-piperazin-1-yl)-N-(1H-indazol-6-yl)-5-nitrobenzamideas a yellow solid.

The nitro compound (0.6 mmol) obtained as above, was reduced underhydrogenation conditions as described in general procedure F to afford4,5-Diamino-2-(3,5-dimethylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toobtain6-(3,5-dimethylpiperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide. MS: m/z 549 (M+H)⁺.

Following the procedure in Example 145,2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide was utilized tosynthesize the compounds listed in Table 11. TABLE 11

MS Ex. Ar R (m/z) 146 2-Trifluoromethylphenyl 2-methoxyethylamino 510147 3-Methylpyridin-2-yl 2-methoxyethylamino 457 1482-Trifluoromethylbenzyl 4-methylpiperazin-1-yl 549 149 Benzyl4-methylpiperazin-1-yl 481 150 Cyclohexylmethyl 4-methylpiperazin-1-yl487 151 Cyclopentyl 4-methylpiperazin-1-yl 459 152(1S,2S,4R)-Bicyclo[2.2.1]hept-2-yl 4-methylpiperazin-1-yl 485 153Adamantan-1-yl 4-methylpiperazin-1-yl 525

Example 154 Synthesis of6-propylamino-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl-amide)

A solution of 2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide (2mmol) in dioxane (4 mL) was reacted with aqueous NH₄OH using theconditions described in Example 115. After the formation of2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide was complete, thevolatiles were removed in vacuo. The residue obtained was suspended incold water with stirring. The solid formed was collected by filtration,washed with water, and dried in vacuo to provide the product,4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide as a yellow solid.

A solution product obtained as above (0.5 mmol) in NMP (1 mL) wascharged with propylamine (0.5 mL). The contents were subjected tomicrowave irradiation at 80° C. for 60 min. The reaction mixture wascooled to room temperature, diluted with water (10 mL). The solid formedwas collected by filtration, washed with water, and dried in vacuo toprovide 4-amino-N-(1H-indazol-6-yl)-5-nitro-2-propylaminobenzamide.

The nitro compound (0.4 mmol) obtained as above was reduced underhydrogenation conditions as described in general procedure F to afford4,5-diamino-N-(1H-indazol-6-yl)-2-propylamino-benzamide.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B to6-propylamino-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)amide. MS: m/z 494 (M+H)⁺.

Example 155 Synthesis of{1-[6-(1H-Indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester

A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1mmol; see Example 154) in NMP (2 mL) was added piperidin-4-yl-carbamicacid tert-butyl ester (4 mmol). The resulting mixture was heated at 100°C. for 10 h. The reaction mixture was cooled to room temperature, anddiluted with water (20 mL). The solid formed was collected byfiltration, washed with water, and dried in vacuo. The crude product waspurified on a silica gel column chromatography using EtOAc/hexane aseluent to provide{1-[5-Amino-2-(1H-indazol-6-ylcarbamoyl)-4-nitro-phenyl]-piperidin-4-yl}-carbamicacid tert-butyl ester as a light yellow solid.

The nitro compound (0.5 mmol) as above was reduced under hydrogenationconditions as described in general procedure F to afford{1-[4,5-diamino-2-(1H-indazol-6-ylcarbamoyl)-phenyl]-piperidin-4-yl}-carbamicacid tert-butyl ester.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide{1-[6-(1H-Indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester. MS: m/z 635 (M+H)⁺.

Example 156 Synthesis of6-(4-Aminopiperidin-1-yl)-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide trihydrochloride

To a solution of{1-[6-(1H-Indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester (0.25 mmol; see Example 155) in methanol (1 mL)was 4M HCl in dioxane (0.5 mL) added. The resulting mixture was stirredat room temperature for 5-6 h. The volatiles were removed in vacuo, andthe residue obtained was suspended in ether. The solid obtained wascollected by filtration, washed with ether and dried in vacuo to afford6-(4-Amino-piperidin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 535(M+H)⁺.

Example 157 Synthesis of{1-[6-(1H-Indazol-6-ylcarbamoyl)-2-(3-methylpyridin-2-ylamino)-3H-benzoimidazol-5-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester

A solution of{1-[4,5-diamino-2-(1H-indazol-6-ylcarbamoyl)-phenyl]-piperidin-4-yl}-carbamicacid tert-butyl ester (0.3 mmol; see Example 155) in DMF (1 mL) wasreacted with 1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol)followed by cyclization in situ using EDC as described in generalprocedure B to provide{{1-[6-(1H-Indazol-6-ylcarbamoyl)-2-(3-methylpyridin-2-ylamino)-3H-benzoimidazol-5-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester. MS: m/z 582 (M+H)⁺.

Example 158 Synthesis of6-(4-Aminopiperidin-1-yl)-2-(3-methyl-pyridin-2-ylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide trihydrochloride

The product from Example 157 was treated with 4M HCl in dioxaneemploying the procedure described for Example 156 to afford6-(4-Aminopiperidin-1-yl)-2-(3-methylpyridin-2-ylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 521(M+H)⁺.

Example 159 Synthesis of[5-(1H-Indazol-6-ylethynyl)-1H-benzoimidazol-2-yl]-(2-trifluoromethyl-phenyl)-amine

A mixture of 4-bromo-2-nitrophenylamine (2.17 g, 10 mmol),ethynyltrimethylsilane (2.11 mL, 98%, 15 mmol),dichlorobis(triphenylphosphine)palladium(II) (211 mg, 0.3 mmol) andcopper(I) chloride (66.5 mg, 0.35 mmol) in THF (10 mL) and triethylamine (10 mL) was stirred at room temperature for 3 days. The product,2-nitro-4-trimethylsilanylethynylphenylamine was purified by silica gelcolumn chromatography. LC-MS m/z: 235 (M+1)⁺.

A mixture of the silyl intermediate from previous above potassiumcarbonate (2.76 g, 20 mmol) and methanol (30 mL) was stirred for twodays. Purification by silica gel column chromatography gave4-ethynyl-2-nitrophenylamine as red solid (1.306 g, 8.05 mmol, yield 81%for 2 steps). LC-MS m/z: 163 (M+1)⁺.

A mixture of 4-ethynyl-2-nitro-phenylamine (1.306 g, 8.05 mmol),6-iodo-1H-indazole (1.965 g, 8.05 mmol),dichlorobis(triphenylphosphine)palladium(II) (122 mg, 0.24 mmol) andcopper(I) chloride (54.4 mg, 0.28 mmol) in THF (8 mL) and triethyl amine(8 mL) was stirred at room temperature overnight. Purification by columnchromatography on silica gel gave4-(1H-indazol-6-ylethynyl)-2-nitrophenylamine as red solid (777 mg, 2.79mmol, yield 35%). LC-MS m/z: 279 (M+1)⁺.

A mixture of the nitro compound from above (774 mg, 2.78 mmol), ironpowder (1.61 g, 97%, 28 mmol) and ammonium chloride (2.25 g, 42 mmol) inethanol (1.5 mL) and water (1.5 mL) was refluxed for 6 h. Purificationby column chromatography on silica gel gave4-(1H-indazol-6-ylethynyl)-benzene-1,2-diamine as brown solid (284 mg,1.14 mmol, yield 41%). LC-MS m/z: 249 (M+1)⁺.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide[5-(1H-Indazol-6-ylethynyl)-1H-benzoimidazol-2-yl]-(2-trifluoromethylphenyl)-amineas yellow solid (178 mg, 0.426 mmol, yield 66%). LC-MS m/z: 418 (M+1)⁺.

Example 160 Synthesis of6-dimethylamino-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1mmol; see Example 157) in DMF (1 mL) was added with of 10% aqueous K₂CO₃solution (0.25 mL). The mixture was then subjected to microwave at 80°C. for 60 min. The contents were cooled to RT and poured into ice-coldwater (20 L). The solid formed was collected by filtration, washed withwater, and dried in vacuo to provide4-amino-2-dimethylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.

The nitro compound (0.5 mmol) as above was reduced under hydrogenationconditions as described in general procedure F to afford4,5-diamino-2-dimethylamino-N-(1H-indazol-6-yl)benzamide.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide6-dimethylamino-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide. MS: m/z 480 (M+H)⁺.

Example 161 Synthesis of6-dimethylamino-2-(3-methylpyridin-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

4,5-diamino-2-dimethylamino-N-(1H-indazol-6-yl)benzamide (see Example160; 0.3 mmol) was reacted with 2-isothiocyanato-3-methylpyridine (0.3mmol; prepared from 2-amino-3-methylpyridine and thiophosgene employingprocedure described in Example 115) followed by cyclization in situusing EDC as described in general procedure B to provide6-dimethylamino-2-(3-methylpyridin-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide. MS: m/z 427 (M+H)⁺.

Example 162 Synthesis of6-(4-methylpiperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid benzothiazol-5-ylamide

5-aminobenzothioazole (4.5 mmol) was reacted with4-chloro-2-fluoro-5-nitrobenzoyl chloride (5 mmol) employing theconditions described in Example 133. The product,N-benzothiazol-5-yl-2-chloro-4-fluoro-5-nitrobenzamide, was alsoisolated similar to Example 133.

A solution of the amide from above (2 mmol) in dioxane (4 mL) wasreacted with aqueous NH₄OH using the conditions described in Example115. After the formation of4-amino-N-benzothiazol-5-yl-2-chloro-5-nitrobenzamide was complete, thereaction mixture was charged with N-methylpiperazine (12 mmol). Thecontents were heated at reflux for 10 h, and the reaction mixture wascooled to RT. The contents were poured onto ice cold water with vigorousstirring. The solid formed was collected by filtration, washed withwater, and dried in vacuo to provide the product,4-amino-N-benzothiazol-5-yl-2-(4-methyl-piperazin-1-yl)-5-nitrobenzamideas a yellow solid.

The nitro compound (2 mmol) obtained as above, was reduced underhydrogenation conditions as described in general procedure F to afford4,5-diamino-N-benzothiazol-5-yl-2-(4-methylpiperazin-1-yl)-benzamide.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toobtain6-(4-methylpiperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid benzothiazol-5-ylamide. MS: m/z 552 (M+H)⁺.

Example 1634-[6-(Benzothiazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]piperazine-1-carboxylicacid tert-butyl ester

A solution of 4-amino-N-benzothiazol-6-yl-2-chloro-5-nitrobenzamide (2mmol; prepared as in Example 141) in dioxane (5 mL) was charged withpiperazine (10 mmol). The contents were heated at reflux for 10 h andthe reaction mixture was cooled to RT. The contents were poured onto icecold water with vigorous stirring. The solid formed was collected byfiltration, washed with water, and dried in vacuo to provide theproduct, 4-amino-N-benzothiazol-6-yl-5-nitro-2-piperazin-1-yl-benzamideas a yellow solid.

The amide (1 mmol) from above was dissolved in THF (3 mL) and wastreated with BOC anhydride (1.2 mmol) and stirred for 2 h at RT. Thesolvent was removed to dryness, and the residue obtained was suspendedin 10% EtOAc/hexane (10 mL) with stirring. The solid formed wascollected by filtration, washed with 10% EtOAc/hexane and dried in vacuoto afford4-[5-amino-2-(benzothiazol-6-ylcarbamoyl)-4-nitrophenyl]piperazine-1-carboxylicacid tert-butyl ester.

The nitro compound (0.8 mmol) as above was reduced under hydrogenationconditions as described in general procedure F to afford4-[4,5-diamino-2-(benzothiazol-6-ylcarbamoyl)-phenyl]piperazine-1-carboxylicacid tert-butyl ester.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide4-[6-(Benzothiazol-6-ylcarbamoyl)-2-(2-trifluoromethylphenylamino)-3H-benzoimidazol-5-yl]piperazine-1-carboxylicacid tert-butyl ester. MS: m/z 638 (M+H)⁺.

Example 164 Synthesis of afford6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid benzothiazol-6-ylamide trihydro chloride

The product from Example 163 was treated with 4M HCl in dioxaneemploying the procedure described for Example 156 to afford6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid benzothiazol-6-ylamide as a hydrochloride salt. MS: m/z 538 (M+H)⁺.

Example 165 Synthesis of4-[6-(Benzothiazol-6-ylcarbamoyl)-2-(3-methylpyridin-2-ylamino)-3H-benzoimidazol-5-yl]piperazine-1-carboxylicacid tert-butyl ester

4-[4,5-diamino-2-(benzothiazol-6-ylcarbamoyl)-phenyl]piperazine-1-carboxylicacid tert-butyl ester (see Example 163; 0.3 mmol) was reacted with2-isothiocyanato-3-methylpyridine (0.3 mmol; prepared from2-amino-3-methylpyridine and thiophosgene employing procedure describedin Example 115) followed by cyclization in situ using EDC as describedin general procedure B to provide4-[6-(Benzothiazol-6-ylcarbamoyl)-2-(3-methyl-pyridin-2-ylamino)-3H-benzoimidazol-5-yl]piperazine-1-carboxylicacid tert-butyl ester. MS: m/z 585 (M+H)⁺.

Example 166 Synthesis of2-(3-Methyl-pyridin-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylicacid benzothiazol-6-ylamide as a hydrochloride salt

The product from Example 165 was treated with 4M HCl in dioxaneemploying the procedure described for Example 156 to afford2-(3-Methyl-pyridin-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylicacid benzothiazol-6-ylamide as a hydrochloride salt. MS: m/z 485 (M+H)⁺.

Example 167 Synthesis of2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylic acidbenzothiazol-6-ylamide

A solution of 3,4-diaminobenzoic acid (3 mmol) in DMF (10 mL) wascharged with 1-isothiocyanato-2-trifluoromethylbenzene (3.3 mmol) andthe resulting solution was stirred at RT for 4 h. After thioureaformation was complete, solid K₂CO₃ (10 mmol) was added to the reactionmixture, and the mixture was heated at 90° C. for 10 h. The reactionmixture was cooled to RT and acidified with 10% aqueous HCl to pH 7. Thecontents were poured onto ice cold water (30 mL) with vigorous stirring.The solid formed was collected by filtration, washed with water, anddried in vacuo to provide the product,2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acid asa yellow solid.

The carboxylic acid obtained as above (0.25 mmol) was coupled with6-aminobenzothiazole (0.25 mmol) using HBTU employing general procedureD. The product,2-(2-Trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylic acidbenzothiazol-6-ylamide, was obtained as a light brown solid afterpurification by silica gel chromatography using DCM/methanol as eluent.MS: m/z 454 (M+H)⁺.

Example 168 Synthesis of6-piperazin-1-yl-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid (5-methyl-1H-indazol-6-yl)amide

To a mixture of 2,4-dimethylaniline (10 mmol) in 5 mL of conc. H₂SO₄,fuming HNO₃ (90%; 0.6 mL) was added dropwise at 0° C. The resultingmixture was stirred for 12 h at RT and then slowly poured into ice. Thesolid was collected by filtration and dried to yield2,4-dimethyl-5-nitroaniline as a yellow solid.

A solution of nitroaniline (5 mmol) obtained as above in HOAc (5 mL) atRT was added with iso-amyl nitrite (6 mmol) dropwise. The resultingmixture was stirred at RT for 14 h and then slowly poured on to coldsaturated aqueous NaHCO₃ solution (15 mL). The contents were extractedwith ethyl acetate (3×20 mL), and the combined organics washed with 5%aqueous Na₂CO₃ solution (30 mL). The volatiles were removed in vacuo togive 6-nitro-5-methylindazole as a brown solid.

The nitro compound (2 mmol) obtained as above was reduced underhydrogenation conditions as described in general procedure F to afford6-amino-5-methylindazole as a brown solid.

The aminoindazole from above (1.5 mmol) was reacted with4-chloro-2-fluoro-5-nitrobenzoyl chloride (1.5 mmol) employing theconditions described in Example 115. The product,2-chloro-4-fluoro-N-(5-methyl-1H-indazol-6-yl)-5-nitrobenzamide, wasalso isolated similar to Example 115.

A solution of the amide from above (1 mmol) in dioxane (2 mL) wasreacted with aqueous NH₄OH using the conditions described in Example115. After the formation of4-amino-2-chloro-N-(5-methyl-1H-indazol-6-yl)-5-nitrobenzamide wascomplete, charged with piperazine (5 mmol). The contents were heated atreflux for 10 h and the reaction mixture was cooled to RT. The contentswere poured onto ice cold water with vigorous stirring. The solid formedwas collected by filtration, washed with water, and dried in vacuo toprovide the product,4-amino-N-(5-methyl-1H-indazol-6-yl)-5-nitro-2-piperazin-1-yl-benzamideas a yellow solid.

The product from above (0.6 mol) was treated with BOC anhydrideemploying the procedure described for Example 163.

The nitro aniline from above (0.5 mmol) was reduced under hydrogenationconditions as described in general procedure F to afford4-[4,5-diamino-2-(5-methyl-1H-indazol-6-ylcarbamoyl)-phenyl]piperazine-1-carboxylicacid tert-butyl ester.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide4-[6-(5-Methyl-1H-indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]piperazine-1-carboxylicacid tert-butyl ester. MS: m/z 635 (M+H)⁺.

The product from above was treated with 4M HCl in dioxane employing theprocedure described for Example 156 to afford6-piperazin-1-yl-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid (5-methyl-1H-indazol-6-yl)amide as a hydrochloride salt. MS: m/z535 (M+H)⁺.

Example 169 Synthesis of4-[2-((1S,2S,4R)-Bicyclo[2.2.1]hept-2-ylamino)-6-(1H-indazol-6-ylcarbamoyl)-3H-benzoimidazol-5-yl]-piperazine-1-carboxylicacid tert-butyl ester

A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1mmol; see Example 154) was reacted with piperazine following theprocedure described in Example 163 to afford4-amino-N-(1H-indazol-6-yl)-5-nitro-2-piperazin-1-ylbenzamide. Theproduct thus obtained was treated with BOC anhydride as in Example 163to obtain4-[5-amino-2-(1H-indazol-6-ylcarbamoyl)-4-nitro-phenyl]-piperazine-1-carboxylicacid tert-butyl ester.

The nitro compound (0.6 mmol) as above was reduced under hydrogenationconditions as described in general procedure F to4-[4,5-diamino-2-(1H-indazol-6-ylcarbamoyl)-phenyl]piperazine-1-carboxylicacid tert-butyl ester.

The diamine (0.3 mmol) from above was reacted with(S)-2-Isothiocyanato-bicyclo[2.2.1]heptane (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide4-[2-((1S,2S,4R)-Bicyclo[2.2.1]hept-2-ylamino)-6-(1H-indazol-6-ylcarbamoyl)-3H-benzoimidazol-5-yl]-piperazine-1-carboxylicacid tert-butyl ester. MS: m/z 571 (M+H)⁺.

Example 170 Synthesis of2-((1S,2S,4R)-Bicyclo[2.2.1]hept-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)amide trihydrochloride

The product from Example 169 was treated with 4M HCl in dioxaneemploying the procedure described for Example 156 to afford2-((1S,2S,4R)-bicyclo[2.2.1]hept-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)amide as a hydrochloride salt. MS: m/z 471 (M+H)⁺.

Example 171 Synthesis of6-Chloro-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)amide

A solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (2mmol; see Example 154) in ethanol (5 mL) and AcOH (1 mL) was added withiron powder (10 mmol). The reaction mixture was then heated to refluxfor 6 h. The contents were cooled to RT, filtered through Celite pad,and the pad washed with ethanol. The filtrates were combined andconcentrated in vacuo. The residue obtained was purified on a silica gelcolumn chromatography using MeOH/DCM as eluent to afford4,5-diamino-2-chloro-N-(1H-indazol-6-yl)benzamide.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide6-chloro-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)amide. MS: m/z 471 (M+H)⁺.

Example 172 Synthesis of2-((1S,2S,4R)-bicyclo[2,2,1]hept-2-ylamino)-6-chloro-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)amide

4,5-Diamino-2-chloro-N-(1H-indazol-6-yl)benzamide (0.3 mmol; see Example171) was reacted with (1S,2S,4R)-2-Isothiocyanato-bicyclo[2.2.1]heptane(0.3 mmol) followed by cyclization in situ using EDC as described ingeneral procedure B to provide2-((1S,2S,4R))-bicyclo[2.2.1]hept-2-ylamino)-6-chloro-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)amide. MS: m/z 421 (M+H)⁺.

Example 173 Synthesis of6-[4-(2-hydroxyethyl)-piperazin-1-yl]-2-(2-trifluoromethyl-phenylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)amide

To a solution of6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide trihydrochloride (0.2 mmol; see Example 88)in methanol (2 mL) was added glyceraldehyde (2 mmol), and the resultingmixture was stirred at RT for 60 min. The reaction mixture was thencharged with solid sodium cyanoborohydride (1 mmol), and the stirringwas continued at RT for 10h. The reaction mixture was then concentratedin vacuo, and the residue was suspended in water (10 mL) with vigorousstirring. After 30 min, the solid was filtered, washed with water, anddried under vacuum to afford6-[4-(2-hydroxyethyl)-piperazin-1-yl]-2-(2-trifluoromethyl-phenylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)amide as a white solid. MS: m/z 565 (M+H)⁺.

Example 174 Synthesis of{4-[6-(1H-indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperazin-1-yl}aceticacid

To a solution of6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide trihydrochloride (0.25 mmol; see Example88) in methanol (1 mL) was added glyoxylic acid (0.5 mmol), and theresulting mixture was stirred at RT for 60 min. The reaction mixture wasthen charged with solid sodium cyanoborohydride (0.6 mmol), and thestirring was continued at RT for 10 h. To the reaction mixture was thenadded a few drops of glacial acetic acid, and the mixture was stirredfor 30 min. The volatiles were then removed in vacuo, and the residuewas suspended in water (10 mL) with vigorous stirring. After 30 min, thesolid was filtered, washed with water, and dried under vacuum to afford{4-[6-(1H-indazol-6-ylcarbamoyl)-2-(2-trifluoromethyl-phenylamino)-3H-benzoimidazol-5-yl]-piperazin-1-yl}aceticacid as a white solid. MS: m/z 579 (M+H)⁺.

Example 175 Synthesis of6-(4-Dimethylsulfamoyl-piperazin-1-yl)-2-(2-trifluoromethyl-phenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

A solution of6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide trihydrochloride (0.3 mmol; see Example 88)in DMF (1 mL) was added with triethylamine (1.5 mmol) andN,N-dimethylsulfamoyl chloride (0.4 mmol). The resulting mixture wasstirred at RT for 4 h and added with hydrazine hydrate (2 mmol). Thecontents were warmed to 50° C. and stirred vigorously for 60 min. Thereaction mixture was then poured into ice cold water, and the solid wasfiltered, washed with water, and dried under vacuum. The crude productwas then purified on a silica gel column chromatography using MeOH/DCMas eluent to afford6-(4-dimethylsulfamoyl-piperazin-1-yl)-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide as a white solid. MS: m/z 628 (M+H)⁺.

Example 176 Synthesis of{6-[5-(1H-Indazol-6-yl)-1H-imidazol-2-yl]-1H-benzimidazol-2-yl}-(2-trifluoromethylphenyl)-amine

Methyl-3-nitroacetophenone (10 mmol) was reduced under hydrogenationconditions as described in general procedure F to afford1-(3-amino-4-methylphenyl)ethanone (1.4 g).

Concentrated HCl (2 mL) was added to a mixture of1-(3-amino-4-methylphenyl)ethanone (8.4 mmol) and NaBF₄ (1.2 g, 11 mmol)in H₂O (10 mL) and the solution was cooled to 0° C. A solution of NaNO₂(0.58 g, 8.4 mmol) in H₂O (1.5 mL) was added dropwise and the mixturewas stirred at 0° C. for 30 min. The solid that formed was collected byfiltration and washed with H₂O (5 mL) followed by Et₂O (5 mL) and driedunder a reduced pressure. CH₂Cl₂ (20 mL), KOAc (0.91 g, 9.3 mmol) and18-crown-6 (50 mg, 0.2 mmol) was added to the solid and the mixture wasstirred at room temperature for 4 h. H₂O (20 mL) was added and thelayers were separated. The organic layer was dried (MgSO₄) and thesolvent removed at reduced pressure to afford1-(1H-indazol-6-yl)ethanone (0.52 g).

Pyrrolidone hydrotribromide (1.8 g, 3.6 mmol) was added to a solution of1-(1H-indazol-6-yl)ethanone (0.5 g, 3 mmol) in THF (10 mL) and thesolution was heated at reflux for 2 h. The solution was allowed to coolto room temperature and H₂O (30 mL) was added and the mixture wasextracted with EtOAc (3×20 mL) and dried (MgSO₄). The solvent wasremoved at reduced pressure to afford2-bromo-1-(1H-indazol-6-yl)-ethanone, which was used directly in thenext step with no purification.

DIEA (0.7 mL, 3.6 mmol) was added to a solution of2-bromo-1-(1H-indazol-6-yl)ethanone (3 mmol) and 4-amino-3-nitrobenzoicacid (0.643 g, 3.5 mmol) in DMF (10 mL) and the solution was stirred atroom temperature for 2 h. NH₄OAc (5 g, 65 mmol) was added to thesolution, followed by HOAc (10 mL) and the mixture was stirred at 140°C. for 2 h. The mixture was cooled to room temperature and poured intoH₂O (30 mL). The precipitate was collected by filtration, washed withH₂O (10 mL) and dried under reduced pressure to afford4-[5-(1H-indazol-6-yl)-1H-imidazol-2-yl]-2-nitrophenylamine (0.56 g).

The nitro aniline from above (1 mmol) was reduced under hydrogenationconditions as described in general procedure F to afford4-[5-(1H-indazol-6-yl)-1H-imidazol-2-yl]-benzene-1,2-diamine.

The diamine (0.5 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.5 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide{6-[5-(1H-Indazol-6-yl)-1H-imidazol-2-yl]-1H-benzimidazol-2-yl}-(2-trifluoromethylphenyl)-amine.MS: m/z 460 (M+H)⁺.

Example 177 Synthesis of6-(2-dimethylamino-ethylsulfanyl)-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

NaH (2 mmol) was added to a solution of 2-dimethylaminoethanethiol (2mmol) in NMP (2 mL), and the mixture was stirred at room temperature for10 min. 4-Amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol;see Example 154) was added to the mixture, and the mixture was stirredat 60-65° C. for 3 h. Water (4 mL) was added to the mixture, and themixture was extracted with EtOAc (3×10 mL) and dried over MgSO₄. Thecombined extracts were dried (MgSO₄), and the solvent was removed atreduced pressure to afford the desired product,4-amino-2-(2-dimethylaminoethylsulfanyl)-N-(1H-indazol-6-yl)-5-nitro-benzamide,which was used without further purification.

The nitro aniline from above (1 mmol) was reduced under hydrogenationconditions as described in general procedure F to afford4,5-diamino-2-(2-dimethylaminoethylsulfanyl)-N-(1H-indazol-6-yl)-benzamide.

The diamine (0.5 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.5 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide6-(2-dimethylaminoethylsulfanyl)-2-(2-trifluoromethylphenylamino)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide. MS: m/z 540 (M+H)⁺.

Example 178 Synthesis of5-ethyl-8-(1H-indazol-6-yl)-2-(2-trifluoromethylphenylamino)-5,6,7,8-tetrahydro-3H-1,3,5,8-tetraazacyclohepta[f]inden-9-one

To a solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide(5 mmol; see Example 154) in dioxane (10 mL) was added2-ethylaminoethanol (15 mmol). The resulting mixture was heated atreflux for 10 h. The reaction mixture was cooled to room temperature anddiluted with water (20 mL). The solid formed was collected byfiltration, washed with water, and dried in vacuo. The product,4-amino-2-[ethyl(2-hydroxyethyl)amino]-N-(1H-indazol-6-yl)-5-nitrobenzamide,was used without any purification.

MeSO₂Cl (0.5 mL, 6.3 mmol) was added dropwise to a solution of thenitroaniline from above (1 g, 3.0 mmol) in THF (10 mL) containing DIEA(1.6 mL) and pyridine (1.5 mL). The solution was stirred at roomtemperature for 1 h and poured into water (10 mL). The mixture wasextracted with EtOAc (3×10 mL), and the combined extracts were driedover MgSO₄. The solvent was removed under reduced pressure to affordmethanesulfonic acid2-{[5-amino-2-(1-methanesulfonyl-1H-indazol-6-ylcarbamoyl)-4-nitrophenyl]ethylamino}ethylester (1.4 g, 2.6 mmol).

NaH (60%, 266 mg, 6.7 mol) was added to a solution of crudemethanesulfonic acid2-{[5-amino-2-(1-methanesulfonyl-1H-indazol-6-ylcarbamoyl)-4-nitrophenyl]ethylamino}ethylester (2.6 mmol) in THF (10 mL) at room temperature. The solution wasstirred at reflux for 3 h. The solvent was removed under reducedpressure, and the residue was taken up in EtOAc and washed with water(10 mL). The organic layer was separated, dried over MgSO₄, and thesolvent was removed under reduced pressure to afford8-amino-1-ethyl-4-(1-methanesulfonyl-1H-indazol-6-yl)-7-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one(1.1 g, 2.5 mmol).

Hydrazine (0.6 mL) was added to a solution of8-amino-1-ethyl-4-(1-methanesulfonyl-1H-indazol-6-yl)-7-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one(1.1 g, 2.5 mmol) in 1:1 THF/MeOH (20 mL). The solution was stirred atroom temperature for 16 h. The solvent was removed under reducedpressure to afford8-amino-1-ethyl-4-(1H-indazol-6-yl)-7-nitro-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-one(815 mg).

The nitro aniline from above (1 mmol) was reduced under hydrogenationconditions as described in general procedure F to afford7,8-Diamino-1-ethyl-4-(1H-indazol-6-yl)-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-one.

The diamine (0.5 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.5 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide5-ethyl-8-(1H-indazol-6-yl)-2-(2-trifluoromethylphenylamino)-5,6,7,8-tetrahydro-3H-1,3,5,8-tetraazacyclohepta[f]inden-9-one.MS: m/z 506 (M+H)⁺.

Example 179 Synthesis of6-imidazol-1-yl-2-(2-trifluoromethylphenylamino)-3H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

To a solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide(1 mmol; see Example 154) in NMP (2 mL) was added with imidazole (5mmol). The resulting mixture was subjected to microwave irradiation at120° C. for 2 h. The reaction mixture was cooled to room temperature anddiluted with water (30 mL). The solid formed was collected byfiltration, washed with water, and dried in vacuo. The product,4-amino-2-imidazol-1-yl-N-(1H-indazol-6-yl)-5-nitro-benzamide, obtainedas a yellow solid was used without any purification.

The nitro compound (0.5 mmol) obtained as above, was reduced underhydrogenation conditions as described in general procedure F to afford4,5-diamino-2-imidazol-1-yl-N-(1H-indazol-6-yl)-benzamide.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide6-imidazol-1-yl-2-(2-trifluoromethylphenylamino)-3H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide. MS: m/z 503 (M+H)⁺.

Example 180 Synthesis of2-(2-trifluoromethylphenylamino)-benzooxazole-5-carboxylic acid(1H-indazol-6-yl)-amide

Following the general Procedure E, 4-Hydroxy-3-nitrobenzoic acid (5mmol) and 6-aminoindazole (5 mmol) were utilized to prepare4-hydroxy-N-(1H-indazol-6-yl)-3-nitrobenzamide as a yellow solid.

The nitrophenol (3 mmol) obtained as above, was reduced underhydrogenation conditions as described in general procedure F to afford3-amino-4-hydroxy-N-(1H-indazol-6-yl)-benzamide.

A solution of the aminophenol (0.5 mmol) from above in DMF (2 mL) wasadded with 1-isothiocyanato-2-trifluoromethylbenzene (0.6 mmol) and DIEA(1 mmol). The reaction mixture was subjected to microwave irradiation at120° C. for 1 h. The reaction mixture was cooled to room temperature,diluted with water (20 mL). The solid formed was collected byfiltration, washed with water, and dried in vacuo. The crude product waspurified on a silica gel column chromatography using MeOH/DCM as eluentto provide 2-(2-trifluoromethylphenylamino)-benzooxazole-5-carboxylicacid (1H-indazol-6-yl)-amide, obtained as a yellow solid. MS: m/z 438(M+H)⁺.

Example 181 Synthesis of2-(1-benzyl-1H-imidazol-2-ylamino)-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

A solution of 2-chloro-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide (10mmol) in dioxane (20 mL) was reacted with aqueous NH₄OH using theconditions described in Example 115. After the formation of2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide was complete, thereaction mixture was charged with N-methylpiperazine (40 mmol) (NMP).The contents were heated at reflux for 10 h, and the reaction mixturewas cooled to RT. The contents were poured onto ice cold water withvigorous stirring. The solid formed was collected by filtration, washedwith water, and dried in vacuo to provide the product,4-amino-N-(1H-indazol-6-yl)-2-(4-methylpiperazin-1-yl)-5-nitrobenzamideas a yellow solid.

The nitro compound (6 mmol) obtained as above, was reduced underhydrogenation conditions as described in general procedure F to afford4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide.

Benzylbromide (3 mmol) and K₂CO₃ (6 mmol) were added to a solution of2-nitroimidazole (2 mmol) in DMF (6 mL). The mixture was stirred at60-70° C. for 4 h or overnight. The contents were cooled to roomtemperature, and water (30 mL) was added. The mixture was extracted withEtOAc (3×15 mL). The combined extracts were dried over MgSO₄, filtered,and the solvent was removed in vacuo to afford1-benzyl-2-nitro-1H-imidazole. The product used for furthertransformation without further purification.

The nitroimidazole (1.5 mmol) from above reduced using iron powder andammonium chloride employing the procedure described in Example 159 toyield 1-benzyl-2-amino-1H-imidazole which was used without anypurification.

The aforementioned aminoimidazole derivative was converted to1-benzyl-2-isothiocyanato-1H-imidazole following the general procedureA.

The isothiocyanate (1 mmol) from above was reacted with3,4-diamino-N-(1H-indazol-6-yl)-benzamide (1 mmol) followed bycyclization using EDC as described in general procedure B to2-(1-benzyl-1H-imidazol-2-ylamino)-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide. MS: m/z 547 (M+H)⁺.

Example 182 Synthesis of4-[2-(1-cyclopentyl-1H-imidazol-2-ylamino)-6-(1H-indazol-6-ylcarbamoyl)-3H-benzoimidazol-5-yl]-piperazine-1-carboxylicacid tert-butyl ester

Bromocyclopentane (14 mmol) and 2-nitroimidazole (10 mmol) were used toprepare 1-cyclopentyl-2-nitro-1H-imidazole following the alkylationprocedure described for Example 181. The product, thus obtained wasreduced under hydrogenation conditions as described in general procedureF to afford 1-cyclopentyl-2-amino-1H-imidazole. This aminoimidazolederivative was converted to 1-cyclopentyl-2-isothiocyanato-1H-imidazolefollowing the general procedure A.

The isothiocyanate (1 mmol) from above was reacted with4-[4,5-diamino-2-(1H-indazol-6-ylcarbamoyl)-phenyl]piperazine-1-carboxylicacid tert-butyl ester (1 mmol; see Example 169) followed by cyclizationusing EDC as described in general procedure B to4-[2-(1-cyclopentyl-1H-imidazol-2-ylamino)-6-(1H-indazol-6-ylcarbamoyl)-3H-benzoimidazol-5-yl]-piperazine-1-carboxylicacid tert-butyl ester. MS: m/z 611 (M+H)⁺.

Example 183 Synthesis of2-(1-cyclopentyl-1H-imidazol-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)amide trihydrochloride

The product from Example 182 was treated with 4M HCl in dioxaneemploying the procedure described for Example 156 to afford2-(1-cyclopentyl-1H-imidazol-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylicacid (1H-indazol-6-yl)amide as a hydrochloride salt. MS: m/z 511 (M+H)⁺.

Example 184 Synthesis of2-(1-cyclopentyl-1H-imidazol-2-ylamino)-6-(4-isopropylpiperazin-1-yl)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)amide

To a solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide(1 mmol; see Example 154) in dioxane (2 mL) was added withN-isopropylpiperazine (4 mmol). The resulting mixture was heated atreflux for 10 h. The reaction mixture was cooled to room temperature anddiluted with water (20 mL) with vigorous stirring. The solid formed wascollected by filtration, washed with water, and dried in vacuo toprovide the product,4-amino-N-(1H-indazol-6-yl)-2-(4-isopropyl-piperazin-1-yl)-5-nitro-benzamideas a yellow solid.

The nitro compound (0.5 mmol) as above was reduced under hydrogenationconditions as described in general procedure F to afford4,5-diamino-N-(1H-indazol-6-yl)-2-(4-isopropylpiperazin-1-yl)-benzamide.

The diamine (0.3 mmol) from above was reacted with to1-cyclopentyl-2-isothiocyanato-1H-imidazole (0.3 mmol; see Example 182)followed by cyclization in situ using EDC as described in generalprocedure B to provide2-(1-cyclopentyl-1H-imidazol-2-ylamino)-6-(4-isopropylpiperazin-1-yl)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)amide. MS: m/z 553 (M+H)⁺.

Following the procedure in Example 184,4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide was utilized tosynthesize the compounds listed in Table 13. TABLE 13

MS Ex. R (m/z) 185 4-ethylpiperazin-1-yl 539 186(2-dimethylaminoethyl)-methylamino 527 187 4-methyl[1,4]diazepan-1-yl539

Using 1-alkyl-2-isothiocyanato-1H-imidazole (prepared using theprocedure in Example 182) and4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide(see Example 181), following compounds (Table 14) were synthesizedemploying the general procedure B: TABLE 14

MS Ex. R (m/z) 188 Cyclohexyl 539 189 Methyl 471 190 Cyclohexylmethyl553 191 Isobutyl 513 192 Cyclobutyl 511 193 1-Ethylpropyl 527 194n-Butyl 513 195 2-Methoxyethyl 515 196 Ethyl 485

Using 1-alkyl-2-isothiocyanato-1H-imidazole (prepared using theprocedure in Example 182) and4,5-Diamino-N-benzothiazol-6-yl-2-(4-methylpiperazin-1-yl)-benzamide(see Example 141), following compounds (Table 15) were synthesizedemploying the general procedure B: TABLE 15

MS Ex. R (m/z) 197 2-Methoxyethyl 532 198 Ethyl 502

Example 199 Synthesis of2-(1-cyclopentyl-1H-imidazol-2-ylamino)-6-(4-methylpiperazin-1-yl)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-5-yl)-amide

5-aminobenzothioazole (5 mmol) was reacted with4-chloro-2-fluoro-5-nitrobenzoyl chloride (5 mmol) employing theprocedure described in Example 115. The product,2-chloro-4-fluoro-N-(1H-indazol-5-yl)-5-nitrobenzamide, was used forfurther transformation without any purification.

A solution of 2-chloro-4-fluoro-N-(1H-indazol-5-yl)-5-nitrobenzamide (2mmol) in dioxane (4 mL) was reacted with aqueous NH₄OH using theconditions described in Example 115. After the formation of2-amino-4-fluoro-N-(1H-indazol-6-yl)-5-nitrobenzamide was complete, thereaction mixture was charged with N-methylpiperazine (8 mmol). Thecontents were heated at reflux for 10 h, and the reaction mixture wascooled to RT. The contents were poured onto ice cold water with vigorousstirring. The solid formed was collected by filtration, washed withwater, and dried in vacuo to provide the product,4-amino-N-(1H-indazol-5-yl)-2-(4-methylpiperazin-1-yl)-5-nitrobenzamideas a yellow solid.

The nitro compound (1 mmol) obtained as above, was reduced underhydrogenation conditions as described in general procedure F to afford4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-5-yl)-benzamide.

The diamine (0.3 mmol) from above was reacted with to1-cyclopentyl-2-isothiocyanato-1H-imidazole (0.3 mmol; see Example 182)followed by cyclization in situ using EDC as described in generalprocedure B to provide2-(1-cyclopentyl-1H-imidazol-2-ylamino)-6-(4-methyl-piperazin-1-yl)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-5-yl)-amide. MS: m/z 525 (M+H)⁺.

The procedure described in Example 199 was adapted to synthesize thefollowing compounds in Table 16 TABLE 16

MS Ex. Ar (m/z) 200 1H-benzotriazol-5-yl 526 201 Benzothiazol-6-yl 542202 2-Oxo-2,3-dihydro-1H-indol-5-yl 540 203 1H-indol-6-yl 524 2043H-benzoimidazol-5-yl 525 205 Benzothiazol-5-yl 542

Example 206 Synthesis of 2-(1-thietan-3-yl-1H-imidazol-2-ylamino)-6-(4-methylpiperazin-1-yl)-1H-1-benzoimidazole-5-carboxylicacid (1H-indazol-5-yl)-amide

2-Nitroimidazole (0.5 g, 4.4 mmol) was added to a solution of KOH (6.6mmol) in water (10 mL). 2-(Chloromethyl)thiirane (0.72 g, 6.6 mmol) wasadded to the solution and the solution was stirred at 65-70° C. for 1 h.The solvent was removed by distillation and the residue was purified byflash column chromatography with CH₂Cl₂ as eluent to afford 0.43 g ofdesired product 2-nitro-1-thietan-3-yl-1H-imidazole (52%).

The nitro compound (2 mmol) obtained as above, was reduced underhydrogenation conditions as described in general procedure F to2-amino-1-thietan-3-yl-1H-imidazole.

The aforementioned aminoimidazole derivative was converted to1-thietan-3-yl -2-isothiocyanato-1H-imidazole following the generalprocedure A.

4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide(0.5 mmol; see Example 181) was reacted with 1-thietan-3-yl-2-isothiocyanato-1H-imidazole (0.5 mmol) followed by cyclization insitu using EDC as described in general procedure B to provide2-(1-thietan-3-yl-1H-imidazol-2-ylamino)-6-(4-methylpiperazin-1-yl)-1H-benzoimidazole-5-carboxylicacid (1H-indazol-5-yl)-amide. MS: m/z 529 (M+H)⁺.

Example 207 Synthesis of2-amino-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide hydrobromide

To a solution of4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide (2mmol; see Example 181) in 10% aqueous EtOH (6 mL) was added cyanogenbromide (2.2 mmol), and the mixture was heated at reflux for 4 h. Thereaction mixture was then concentrated in vacuo, and the residueobtained was suspended in diethyl ether with vigorous stirring. Thesolid obtained was collected by filtration, washed with diethyl ether,and dried in vacuo to afford2-amino-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide as a hydrobromide salt. MS: m/z 391 (M+H)⁺.

Example 208 Synthesis of2-(3-cyclopentyl-3-ethylureido)-6-(4-methyl-piperazin-1-yl)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

A solution of cyclopentylethylamine (3 mmol) in anhydrous THF (3 mL) wasadded dropwise to a solution of phosgene (4 mmol) at 0° C. After theaddition was complete, the reaction mixture was stirred for 30 min at 0°C. The volatiles were removed in vacuo, and the residue obtained wasdried under vacuum. The crude product, cyclopentylethylcarbamoylchloride was used for further transformation without any purification.

A solution of afford2-amino-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide hydrobromide (0.5 mmol) in DMF (2 mL) was addedwith DIEA (2 mmol) followed by the carbamoyl chloride (0.6 mmol),obtained as above, at RT. The resulting mixture was stirred for 4 h.Hydrazine hydrate (0.25 mL) was added to the reaction mixture. Thecontents were warmed to 50° C. and stirred for 60 min. The reactionmixture was then cooled to RT, diluted with ice cold water (10 mL) andextracted with EtOAc (2×10 mL). The combined extracts were washed withwater (10 mL) and brine (10 mL). After removal of the solvent, theresidue obtained was purified on a silica gel column chromatography toyield2-(3-cyclopentyl-3-ethylureido)-6-(4-methyl-piperazin-1-yl)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide. MS: m/z 530 (M+H)⁺.

Example 209 Synthesis of2-mercapto-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide

To a solution of4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide(0.5 mmol; see Example 181) in DMF (1 mL) was added thiocarbonyldiimidazole (0.55 mmol). Following the addition, the mixture was warmedat 45° C. for 1 h. The reaction mixture was cooled to RT, and thecontents were poured onto ice cold water with vigorous stirring. Thesolid formed was collected by filtration, washed with water, and driedin vacuo to provide the product,2-mercapto-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylic acid(1H-indazol-6-yl)-amide as a yellow solid.

Example 210 Synthesis of2-(1-cyclopentyl-1H-benzimidazol-2-ylamino)-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide

A solution of 2-fluoro-1-nitrobenzene (2 mmol) in THF was added withcyclopentylamine (2.5 mmol) and K₂CO₃ (3 mmol). The resulting mixturewas heated at 60° C. for 4 h. The contents were cooled to RT, and thesolid was filtered off. The filtrate was concentrated in vacuo, and theresidue was dried under vacuum. The product,2-cyclopentylamino-1-nitrobenzene, was used for further transformationwithout any purification.

The nitroaniline (2 mmol) obtained as above was reduced underhydrogenation conditions as described in general procedure F toN-cyclopentylbenzene-1,2-diamine.

A solution of the diamine (1.5 mmol) obtained as above in 10% aqueousEtOH (4 mL) was added with cyanogen bromide (1.7 mmol) and was heated atreflux for 4 h. The reaction mixture was then cooled to RT, added withsolid K₂CO₃ (2 mmol) and stirred vigorously for 30 min. The solid wasthen filtered off, and the filtrate was concentrated under vacuum toafford 1-cyclopentyl-1H-benzoimidazol-2-ylamine which was used forfurther transformation without any purification.

The aforementioned aminobenzimidazole (1 mmol) derivative was convertedto 1-cyclopentyl-2-isothiocyanato-1H-benzimidazole following the generalprocedure A.

4,5-diamino-2-(4-methylpiperazin-1-yl)-N-(1H-indazol-6-yl)-benzamide(0.5 mmol; see Example 181) was reacted with1-cyclopentyl-2-isothiocyanato-1H-benzimidazole (0.5 mmol) followed bycyclization in situ using EDC as described in general procedure B to2-(1-cyclopentyl-1H-benzimidazol-2-ylamino)-6-(4-methylpiperazin-1-yl)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide. MS: m/z 575 (M+H)⁺.

Example 211 Synthesis of[6-(1H-indazol-6-yloxy)-1H-benzimidazol-2-yl]-(2-trifluoromethylphenyl)-amine

To a stirred suspension of 6-aminoindazole (20 mmol) in concentrated HCl(6 mL) at 0° C. was added a solution of NaNO₂ (22 mmol) in water (12 mL)in portions. During the addition, the temperature of the reactionmixture was maintained at 0-5° C., and the stirring continued foradditional 45 min. The contents were then added into a flask containing1% aqueous HCl (200 mL), and heated at 100° C. The reaction mixture wasthen stirred at 100° C. for 5 h. The contents were cooled to RT,neutralized to pH 7 using 5% aqueous Na₂CO₃, and extracted with EtOAc(2×70 mL). Combined organic layers were washed with brine and dried overanhydrous Na₂SO₄. Removal of solvent under vacuum provided6-hydroxyindazole as dark brown solid, which was used for furthertransformation without any purification.

To a stirred solution of 2-chloro-4-fluoro-1-nitrobenzene (3 mmol) inDMF (5 mL) was added 6-hydroxyindazole (3 mmol) and K₂CO₃ (6 mmol). Thecontents were heated at 90° C. for 6 h. The reaction mixture was cooledto RT, and the contents were poured onto ice cold water with vigorousstirring. The solid formed was collected by filtration, washed withwater, and dried in vacuo to provide the product,6-(3-chloro-4-nitrophenoxy)-1H-indazole as a yellow solid, which wasused for further transformation without any purification.

A stirred solution of the nitro compound (2 mmol) in DMF (4 mL) wasadded with benzylamine (4 mmol) and contents were heated at 100° C. for6 h. The reaction mixture was cooled to RT and the contents were pouredonto ice cold water with vigorous stirring. The solid formed wascollected by filtration, washed with water, and dried in vacuo. Theresidue obtained was purified on silica gel column chromatography usinghexane/EtOAC as eluent to provide the product,benzyl-[5-(1H-indazol-6-yloxy)-2-nitrophenyl]-amine as a yellow solid.

The nitroaniline (1 mmol) obtained as above was reduced underhydrogenation conditions as described in general procedure F to4-(1H-Indazol-6-yloxy)-benzene-1,2-diamine.

The diamine (0.3 mmol) from above was reacted with1-isothiocyanato-2-trifluoromethylbenzene (0.3 mmol) followed bycyclization in situ using EDC as described in general procedure B toprovide[6-(1H-indazol-6-yloxy)-1H-benzimidazol-2-yl]-(2-trifluoromethylphenyl)-amine.MS: m/z 410 (M+H)⁺.

Example 212 Synthesis of{5-[2-(1H-indazol-6-yl)-ethyl]-1H-benzimidazol-2-yl}-(2-trifluoromethylphenyl)amine

A solution of[5-(1H-Indazol-6-ylethynyl)-1H-benzoimidazol-2-yl]-(2-trifluoromethylphenyl)-amine(0.3 mmol; see Example 159) in ethanol (3 mL) was reduced underhydrogenation conditions at 50 psi as described in general procedure toyield{5-[2-(1H-indazol-6-yl)-ethyl]-1H-benzimidazol-2-yl}-(2-trifluoromethylphenyl)amine.MS: m/z 422 (M+H)⁺.

Example 213 Synthesis of3-[6-Diethylamino-5-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-benzoicacid

To a solution of3-[6-diethylamino-5-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-benzoicacid methyl ester (0.2 mmol; see Example 115) in methanol (2 mL) and THF(2 mL) was added 1M aqueous LiOH solution (2 mL). The resulting solutionwas then stirred at RT until the reaction was complete. The pH of thereaction mixture was adjusted with 5% aqueous citric acid solution tobring its pH to 4-5. The solid obtained was filtered, washed withice-cold water, and dried under vacuum to afford3-[6-diethylamino-5-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-benzoicacid as a white solid. MS: m/z 484 (M+H)⁺.

Example 214 Synthesis of3-[5-(Benzothiazol-6-ylcarbamoyl)-6-diethylamino-1H-benzoimidazol-2-ylamino]-benzoicacid methyl ester

4,5-Diamino-N-benzothiazol-6-yl-2-diethylaminobenzamide (0.3 mmol; seeExample 133) from above was reacted with 3-isothiocyanatobenzoic acidmethyl ester (0.3 mmol) followed by cyclization in situ using EDC asdescribed in general procedure B to obtain3-[5-(benzothiazol-6-ylcarbamoyl)-6-diethylamino-1H-benzoimidazol-2-ylamino]-benzoicacid methyl ester. MS: m/z 515 (M+H)⁺.

Example 215 Synthesis of3-[5-(Benzothiazol-6-ylcarbamoyl)-6-diethylamino-1H-benzoimidazol-2-ylamino]-benzoicacid

The methyl ester (0.2 mmol) from Example 214 was hydrolyzed employingthe conditions described for Example 216 to yield3-[5-(benzothiazol-6-ylcarbamoyl)-6-diethylamino-1H-benzoimidazol-2-ylamino]-benzoicacid as a white solid. MS: m/z 501 (M+H)⁺.

Biological Data

The compounds of the present invention elicit measurable pharmacologicalresponses. The compounds of the present invention in Table 1 have abinding affinity (IC₅₀<1 μM) for aurora kinases and may be selective foraurora kinases as compared to other kinases In addition to the bindingto aurora kinases, compounds of the present invention may alsomeasurably inhibit the proliferation of tumor cells.

Example 216

Aurora A, B, C Enzyme Assays

Aurora kinase assays utilize the peptide substratebiotin-ahx-LRRWSLGLRRWSLG as a phosphoryl group acceptor.

Assays are performed in 96-well U-bottom plates. Aurora A and Aurora Cenzymes are purchased from PanVera, Aurora B enzyme is purchased fromBPS Bioscience. Compounds are diluted in DMSO prior to addition in theassay. Typically, assays are performed by incubating enzyme (0.2-10 nM)with or without inhibitor, 0.1-1 μCi γ³³P-ATP (Perkin Elmer), 0.1-100 μMATP, 0.1-10 mM MnCl₂, 1-10 μM sodium orthovanadate, 1-10 mM DTT, and1-100 μM peptide together for the time range of 5-120 min at 37° C. in afinal assay volume of 60 μL. The buffer used to bring the final assayvolume up to 60 μL is 50 mM MOPS, pH 7.0, containing 1-5% DMSO and 0.05%BSA. Reactions are terminated by addition of 0.2-2 volumes of 0.75%phosphoric acid.

Detection of peptide phosphorylation is accomplished by scintillationcounting using a beta counter (TopCount) following collection of peptideonto P81 96-well filter plates (whatman). Total control cpm (C⁺) andbackground control cpm (C⁻) wells contain DMSO instead of compound.Background control (C⁻) wells lack peptide. Total (C⁺) minus background(C⁻) counts are assumed to be proportional to initial reaction velocity.Percent enzyme inhibition is calculated as1−[(cpm_(sample)−C⁻)/(C⁺−C⁻)]×100%. IC₅₀ values are determined from %enzyme inhibition versus compound concentration curve plots usingGraphPad Prism™ according to the 4 parameter logistic equationY=Bottom+(Top−Bottom)/1+10ˆ((LogEC50−X)*HillSlope)) where X is thelogarithm of compound concentration and Y is percent inhibition.

Each of the compounds in Table 1 exhibited an IC₅₀ value of less than orequal to 1.0 μM for at least one of Aurora kinase A, B or C in the aboveassay.

Example 217

EGF RTK Enzyme Assay

EGF receptor tyrosine kinase assay utilizes the peptide substratebiotin-ahx-EEEEYFELVAKKK-C(O)NH₂ (Advanced Chemtech, # PX9197) asphosphoryl group acceptor.

Assays are performed in 96-well U-bottom plates. The tyrosine kinasedomain of the EGF receptor is purchased from Upstate (#14-531).Compounds are diluted in DMSO prior to addition in the assay. Typically,assays are performed by incubating enzyme (0.2-10 nM) with or withoutinhibitor, 0.1-1 μCi γ³³P-ATP (Perkin Elmer), 0.1-100 μM ATP, 0.1-10 mMMnCl₂, 1-10 μM sodium orthovanadate, 1-10 mM DTT, and 1-100 μM peptidetogether for the time range of 5-120 min at 37° C. in a final assayvolume of 60 μL. The buffer used to bring the final assay volume up to60 μL is 50 mM MOPS, pH 7.0, containing 1-5% DMSO. Reactions areterminated by addition of 0.2-2 volumes of 0.75% phosphoric acid.Compounds are diluted in DMSO prior to addition in the assay.

Detection of peptide phosphorylation is accomplished by scintillationcounting using a beta counter (TopCount) following collection of peptideonto P81 96-well filter plates (Whatman). Total control cpm (C⁺) andbackground control cpm (C⁻) wells contain DMSO instead of compound.Background control (C⁻) wells lack peptide. Total (C⁺) minus background(C⁻) counts are assumed to be proportional to initial reaction velocity.Percent enzyme inhibition are calculated as1−[(cpm_(sample)−C⁻)/(C⁺−C⁻)]×100%. IC₅₀ values are determined from %enzyme inhibition vs compound conc. curve plots using GraphPad Prismaccording to the 4 parameter logistic equationY=Bottom+(Top−Bottom)/1+10ˆ((LogEC50−X)*HillSlope)) where X is thelogarithm of compound concentration and Y is percent inhibition.

Each of the Examples 1-92 in Table 1 exhibited an IC₅₀ value of greaterthan or equal to 3.0 μM this assay.

Example 218

IGF-1 RTK Enzyme Assay

IGF-1 receptor tyrosine kinase assay utilizes the peptide substratebiotin-ahx-EQEDEPEGDYFEWLE-C(O)NH₂ (Synpep) as phosphoryl groupacceptor.

Assays are performed in 384-well black plates (Nunc). The kinase domainof IGF-1 receptor is purchased from Upstate (cat. no. 14-465M). Theenzyme is preactivated on ice for 15 min in the presence of 100 μM ATPand 20 mM MgCl₂. Compounds are diluted in DMSO prior to addition in theassay. Typically, assays are performed by incubating enzyme (0.2-10 nM)with or without inhibitor, 30 μM ATP, 5 mM MgCl₂, 400 nM peptide andincubated for 40 min at 25° C. in a final assay volume of 20 μL. Theassay buffer used is 50 mM Tris-HCl, pH 7.5. Reactions are terminated byaddition of 10 μL of 0.15 M EDTA.

Detection of peptide phosphorylation is accomplished by homogenoustime-resolved fluorescence (HTRF) following addition of 25 μL Eu-W1024labeled anti-phosphotyrosine pTyr-100 (Perkin Elmer) antibody (finalconc. 20 nM) and 25 μL streptavidin-APC (Perkin Elmer, final conc. 20nM) in a total volume of 80 μL. Both HTRF detection reagents are dilutedin 50 mM Tris-HCl, pH 7.5 buffer containing 0.5% BSA. The assay plate isincubated for 15 min at 25° C. and read in the Envision in time-resolvedfluorescence mode with instrument settings for excitation at 340 nm andemission at 665 nM. Total control fluorescence units (C⁺) and backgroundcontrol rfu (C⁻) wells contain DMSO instead of compound. Backgroundcontrol (C⁻) wells lack peptide. Percent enzyme inhibition is calculatedas 1−[(cpm_(sample)−C⁻)/(C⁺−C⁻)]×100%. IC₅₀ values are determined from %enzyme inhibition vs compound conc. curve plots using GraphPad Prism™according to the 4 parameter logistic equationY=Bottom+(Top−Bottom)/1+10ˆ((LogEC50−X)*HillSlope)) where X is thelogarithm of compound concentration and Y is percent inhibition.

Each of the Examples 1-92 in Table 1 exhibited an IC₅₀ value of greaterthan or equal to 3.0 μM this assay.

Example 219

CDK2 Enzyme Assay

CDK2 kinase assay utilizes the peptide substrate Biotin-ahx-ARRPMSPKKKAas phosphoryl group acceptor.

Assays are performed in 96-well U-bottom plates. CDK2 enzyme ispurchased from PanVera. Typically, assays are performed by incubatingenzyme (0.2-10 nM) with or without inhibitor, 0.1-1 μCi γ³³P-ATP (PerkinElmer), 0.1-100 μM ATP, 0.1-10 mM MgCl₂, 1-100 μM sodium orthovanadate,1-10 mM DTT, and 1-100 μM peptide together for the time range of 5-120min at 25° C. in a final assay volume of 60 μL. The buffer used to bringthe final assay volume up to 60 μL is 50 mM Tris-HCl, pH 7.5, containing1-5% DMSO and 0.1% BSA. Reactions are terminated by addition of 0.2-2volumes of 0.75% phosphoric acid. Compounds are diluted in DMSO prior toaddition in the assay.

Detection of peptide phosphorylation is accomplished by scintillationcounting using a beta counter (TopCount) following collection of peptideonto P81 96-well filter plates (Whatman). Total control cpm (C⁺) andbackground control cpm (C⁻) wells contain DMSO instead of compound.Background control (C⁻) wells lack peptide. Total (C⁺) minus background(C⁻) counts are assumed to be proportional to initial reaction velocity.Percent enzyme inhibition is calculated as1−[(cpm_(sample)−C⁻)/(C⁺−C⁻)]×100%. IC₅₀ values were determined from %enzyme inhibition vs compound conc. curve plots using GraphPad Prismaccording to the 4 parameter logistic equationY=Bottom+(Top−Bottom)/1+10ˆ((LogEC50-X)*HillSlope)) where X is thelogarithm of compound concentration and Y is percent inhibition.

Each of the Examples 1-92 in Table 1 exhibited an IC₅₀ value of greaterthan or equal to 3.0 μM this assay.

Example 220

VEGFR-2 TK Enzyme Assay

VEGFR-2 tyrosine kinase assay utilizes the peptide substratebiotin-ahx-EQEDEPEGDYFEWLE-C(O)NH₂ as phosphoryl group acceptor.

The kinase domain of VEGFR-2 is purchased from ProQuinase. The enzyme ispreactivated on ice for 15 min in the presence of 100 μM ATP and 20 mMMgCl₂. Assays are performed in 96-well U-bottom plates. Typically,assays are performed by incubating enzyme (0.2-10 nM) with or withoutinhibitor, 30 μM ATP, 5 mM MgCl₂, and 400 nM peptide together for 30 minat 25° C. in a final assay volume of 20 μL. The buffer used to bring thefinal assay volume up to 20 μL is 50 mM Tris-HCl, pH 7.5. Reactions areterminated by addition of 10 μL of 0.15 M EDTA.

Detection of peptide phosphorylation is accomplished by homogenoustime-resolved fluorescence (HTRF) following addition of 25 μL Eu-W1024labeled anti-phosphotyrosine pTyr-100 (Perkin Elmer) antibody (finalconc. 20 nM) and 25 μL streptavidin-APC ((Perkin Elmer, final conc. 20nM) in a total volume of 80 μL. Both HTRF detection reagents are dilutedin 50 mM Tris-HCl, pH 7.5 buffer containing 0.5% BSA. The assay plate isincubated for 15 min at 25° C. and read in the Envision in time-resolvedfluorescence mode with instrument settings for excitation at 340 nm andemission at 665 nM. Positive control (C⁺) and negative control (C⁻)wells contain DMSO instead of compound. Negative control (C⁻) wells lackpeptide. Percent enzyme inhibition is calculated as1−[(RFU_(sample)−C⁻)/(C⁺−C⁻)]×100%. IC₅₀ values are determined from the% enzyme inhibition vs compound conc. curve plots using GraphPad Prism™according to the 4 parameter logistic equationY=Bottom+(Top−Bottom)/1+10ˆ((LogEC50−X)*HillSlope)) where X is thelogarithm of compound concentration and Y is percent inhibition.

Each of the Examples 1-92 in Table 1 exhibited an IC₅₀ value of greaterthan or equal to 3.0 μM this assay.

Example 221

In Vitro Cell Proliferation

Compounds are tested for their ability to inhibit cell proliferation andviability. The metabolic reduction of alamarBlue™ (Biosource cat. no.DAL1100) was used to measure cell viability.

The anti-proliferative activity of compounds is studied using a panel oftumor cells: HCT-116 (human colorectal carcinoma cell line), BxPC-3(human pancreatic adenocarcinoma cell line), A549 (human lung carcinomacell line), BT-549 (human breast carcinoma cell line), LNCaP (humanprostate carcinoma cell line), and MIA Paca-2 (human pancreaticcarcinoma cell line). These adherent cells (1,000-20,000) are plated incomplete media (RPMI-1640, DMEM, F12K, or McCoy's 5A) containing 10%fetal bovine serum (Gibco) in tissue culture treated 96-well plates(Costar) and placed in a humidified incubator at 37° C., 95% O₂, 5% CO₂for 18-24 hr. Media was removed and replaced with 90 μL fresh media.Compound is diluted in media containing 3% DMSO and added to cells.Background (C⁻) relative fluorescent units are determined by incubatingalamarBlue™ reagent for 6 hr using untreated cells plated 18 hr earlier.Untreated cells or cells containing compound are incubated for 96 hr.During the last 6 hr of the incubation period, alamarBlue™ reagent (10μL) was added to each well and incubated in a humidified incubator at37° C., 95% O₂, 5% CO₂.

AlamarBlue™ reduction is measured in a fluorescence plate reader withinstrument settings for excitation at 530 nm and emission at 590 nm.Percent inhibition of cell growth was calculated as1−[(RFU_(sample)−C⁻)/(RFU_(untreated)−C⁻)]×100%. Compound IC₅₀ valuesare determined from % inhibition versus compound concentration curveplots using GraphPad Prism™ according to the 4 parameter logisticequation Y=Bottom+(Top−Bottom)/1+10ˆ((LogEC50−X)*HillSlope)).

Various compounds in Table 1 exhibited an IC₅₀ value of less than orequal to 3.0 μM against one or more of the panel of tumor cells. Inparticular, Examples 27, 35, 36, 48, 50, 54, 57, 58, and 60 had an IC₅₀value of less than or equal to 3 μM against at least one of HCT-116, MIAPaca-2, or LNCaP cells in using the assay conditions described above.

Drug Combination Pharmacology Studies

While the compounds of the present invention may be used as a singleagent, they may also be used as part of a combination therapy. Forexample, Example 88 when administered as a single agent demonstratedantitumor activity in established human tumor xenografts in athymic miceincluding tumors derived from pancreas and breast tissues (See singleagent dose curves for Example 88 in Examples 222-224 below). To evaluatethe therapeutic efficacy of Example 88 in combination with othertherapeutic agents and to identify potential synergistic interactions,various studies in animals were performed using Example 88 incombination with Gemcitabine (Gemzar™), erlotinib (Tarceva™), ortrastuzumab (Herceptin™).

Gemcitabine, erlotinib, and trastuzumab are therapeutic agents that cantreat a spectrum of solid tumors. Each of gemcitabine, erlotinib, andtrastuzumab have different proposed mechanisms of action from each otherand from the compounds of the present invention. Gemcitabine is aninhibitor of DNA synthesis via inhibition of the enzyme ribonucleotidereductase. Erlotinib is an EGF receptor tyrosine kinase inhibitor thatblocks EGF growth factor function. Gemcitabine and erlotinib arecurrently used for the treatment of advanced pancreatic cancer.Trastuzumab is a recombinant humanized monoclonal antibody that bindsand blocks p185^(HER2) receptor function. Trastuzumab is first linetreatment for patients with metastatic breast carcinoma whose tumorsoverexpress the HER2 protein.

Example 222

The antitumor activity of Example 88 administered alone and incombination with erlotinib was evaluated against established humanMiaPaCa-2 pancreatic xenografts in athymic mice (a preclinical model ofpancreatic cancer). Compounds were dosed on the following schedules:

1) Example 88 was dosed i.p., b.i.d. daily for 10 days (days 1-10).

2) Erlotinib was dosed 50 mg/kg, p.o., daily for 14 days (days 1-14).

The anti-tumor activity was evaluated by inhibition of tumor growth andby assessment of the regression of individual tumors characterized byeither partial (greater than 50% reduction in tumor size) or completeresponses (100% reduction in tumor size).

Drug treatment started when mean tumor sizes reached approximately 120mg (day 8). Mice-bearing sc tumors were randomized, and treatment groupsconsisted of 8 mice. The median tumor size for each group at variouspoints in the study are listed below in Table A. TABLE A MiaPaCa-2Xenograft Model Example 88 Example 88 Day Vehicle alone Erlotinib aloneand Erlotinib of Median Tumor Median Tumor Median Tumor Median TumorStudy Size (mg) Size (mg) Size (mg) Size (mg) 8 113 120 120 120 10 171162 144 162 13 192 170 192 162 16 241 170 267 108 20 435 221 363 82 23609 209 507 69 27 988 368 700 88 30 1282 486 908 101 34 1521 817 1224148 37 1770 1055 1296 225 42 2058 1629 1368 398The MiaPaCa-2 tumor growth curves are shown in FIG. 1, where

-   -   ▴—represents vehicle for Example 88 and erlotinib;    -   ◯—represents erlotinib at a dose of 50 mg/kg, p.o., daily for 14        days;    -   □—represents Example 88 at a dose of 10 mg/kg, i.p., b.i.d.        daily for 10 days; and    -   ●—represents Example 88 and erlotinib.

Previous dose response studies in this model found Example 88 (10 mg/kg)was a moderately effective dose for inhibition of tumor growth in thismodel. Example 88 (10 mg/kg) produced 67% inhibition of tumor growthrelative to vehicle-treated tumors on day 23. Erlotinib (50 mg/kg)produced 16% inhibition of tumor growth on day 23. In contrast, theExample 88/erlotinib combination produced 89% inhibition of tumor growthon day 23. Analysis of the individual tumor regression profile on day 42revealed the Example 88/erlotinib combination therapy produced I partialresponder and 2 complete responders out a total of 8 mice (Table AA);however, neither single agent produced a response. TABLE AA Example 88response summary for MIAPaCa-2 xenografts Responder Example 91 ErlotinibExample 91 + Type Vehicle 10 mg/kg 50 mg/kg erlotinib PR 0/8 0/8 0/8 1/8CR 0/8 0/8 0/8 2/8In summary, Example 88 (10 mg/kg) produced higher antitumor responserates in the MiaPaCa-2 model when combined with erlotinib (50 mg/kg)than when either Example 88 or erlotinib was dosed as a single agent.

Example 223

The antitumor activity of Example 88 administered alone and incombination with gemcitabine was evaluated against established humanMiaPaCa-2 pancreatic xenografts in athymic mice (a preclinical model ofpancreatic cancer). Compounds were dosed on the following schedules:

-   -   1) Example 88 was dosed i.p., b.i.d. daily for 10 days (days        1-10).    -   2) Gemcitabine was dosed 120 mg/kg, i.p., q3d×4 (days 1, 4, 7,        10).

The anti-tumor activity was evaluated by inhibition of tumor growth, andby assessment of the regression of individual tumors characterized byeither partial (greater than 50% reduction in tumor size) or completeresponses (100% reduction in tumor size).

Drug treatment started when mean tumor sizes reached approximately 120mg (day 8). Mice-bearing sc tumors were randomized, and treatment groupsconsisted of 8 mice. The median tumor size for each group at variouspoints in the study are listed below in Table B. TABLE B MiaPaCa-2Xenograft Model Vehicle Example 88 Gemcitabine Example 88 and Medianalone alone gemcitabine Day of Tumor Median Tumor Median Tumor MedianTumor Study Size (mg) Size (mg) Size (mg) Size (mg) 8 113 120 120 126 10144 162 144 144 13 192 170 144 170 16 192 170 153 98 20 295 221 221 6923 466 209 246 63 27 650 368 336 86 30 757 486 472 149 34 972 817 675251 37 1132 1055 824 359 42 1353 1629 988 606The MiaPaCa-2 tumor growth curves are shown in FIG. 2, where

-   -   ▪—represents vehicle for Example 88 and gemcitabine;    -   ▴—represents Example 88 at a dose of 10 mg/kg, i.p., b.i.d.        daily for 10 days;    -   □—represents gemcitabine at as dose of 120 mg/kg, i.p., q3d×4;        and    -   ◯—represents Example 88 and gemcitabine.

Previous dose response studies in this model found Example 88 (10 mg/kg)was a moderately effective dose for inhibition of tumor growth in thismodel. Example 88 (10 mg/kg) produced 67% inhibition of tumor growthrelative to vehicle-treated tumors on day 23. Gemcitabine (120 mg/kg)produced 60% inhibition of tumor growth on day 23. In contrast, theExample 88/gemcitabine combination produced 90% inhibition of tumorgrowth on day 23. Analysis of individual tumor regressions on day 42revealed the Example 88/gemcitabine combination therapy produced 1partial responder and 1 complete responder out a total of 8 mice;neither single agent produced a response (Table BB). TABLE BB Example 88response summary for MIAPaCa-2 xenografts Responder Example 88gemcitabine Example 88 + Type Vehicle 10 mg/kg 120 mg/kg gemcitabine PR0/8 0/8 0/8 1/8 CR 0/8 0/8 0/8 1/8In summary, Example 88 (10 mg/kg) produced higher antitumor responserates in the MiaPaCa-2 model when combined with gemcitabine (120 mg/kg)than when either Example 88 or gemcitabine was dosed as a single agent.

Example 224

Trastuzumab is first line treatment for patients with metastatic breastcarcinoma whose tumors overexpress the HER2 protein. Example 88 incombination with trastuzumab was tested in the BT-474 breast xenograftmodel. The drug treatment started when mean tumor sizes reachedapproximately 110 mg (day 35 post implantation). Mice-bearing sc tumorswere randomized, and treatment groups consisted of 10 mice. Compoundswere dosed on the following schedules:

1) Example 88 was dosed 30 mg/kg, i.p., b.i.d. daily for 3 days, then 2days off, for a total of 5 cycles;

2) Trastuzumab was dosed 10 mg/kg, i.p., twice weekly, for 4 weeks.

The medium tumor size for each group at various points in the study arelisted below in Table C. TABLE C BT-474 Xenograft Model Vehicle Example88 Trastuzumab Example 88 and Median alone alone trastuzumab Day ofTumor Median Tumor Median Tumor Median Tumor Study Size (mg) Size (mg)Size (mg) Size (mg) 1 113 113 113 113 4 170 120 133 152 7 190 152 132189 10 259 153 124 225 14 342 179 106 266 17 394 149 80 284 21 504 14254 384 24 617 138 36 416 28 104 18 416

The BT-474 tumor growth curves in athymic SCID mice are shown in FIG. 3where day 1 is when treatment started and where

-   -   ▪—represents vehicle for Example 88;    -   ◯—represents trastuzumab at a dose of 10 mg/kg, i.p., twice        weekly, for 4 weeks;    -   ▴—represents Example 88 at a dose of 30 mg/kg, i.p., b.i.d.        daily for 3 days, then 2 days off, for a total of 5 cycles;    -   □—represents Example 88 and trastuzumab.

Example 88 (30 mg/kg) produced 77% inhibition of tumor growth relativeto vehicle-treated tumors on day 24. Trastuzumab (10 mg/kg) produced 33%inhibition of tumor growth on day 24. In contrast, the Example88/trastuzumab combination produced 94% inhibition of tumor growth onday 24. Analysis of the individual tumor regression profile on day 24revealed the Example 88/trastuzumab combination therapy produced 4partial responders and 6 complete responders out of a total of 10 mice(Table CC); however, neither single agent produced a response. TABLE CCExample 88 response summary for BT-474 xenografts Responder Example 88Trastuzumab Example 88 + Type Vehicle 10 mg/kg 10 mg/kg trastuzumab PR0/10 0/10 0/10 4/10 CR 0/10 0/10 0/10 6/10In summary, the combination of Example 88 (30 mg/kg) and trastuzumab (10mg/kg) produced a superior complete tumor regression rate when comparedwith either Example 88 or trastuzumab alone in the BT-474 xenograftmodel.

The following procedures are for preparing pharmaceutical formulationcontaining a compound of the present invention.

Example 225

A pharmaceutical formulation containing 2.0 mg/mL of Example 88 (whichis equivalent to 2.7 mg/mL of Example 88 as a trihydrochloride salt) wasprepared as follows.

Example 88 as a trihydrochloride salt (1.350 gr) was dissolved withstirring in Sterile Water For Injection (SWFI). The SWFI may be degassedwith sterile nitrogen gas prior to use. The amount of SWFI into whichExample 88 is dissolved is an amount into which the compound willdissolve. In one embodiment, the amount of SWFI into which the compoundis dissolved is above 50% of the final volume and may be 75% of thefinal volume.

D-Mannitol was added to the solution and dissolved with stirring. Priorto the addition of mannitol or after dissolving the mannitol, the pH ofthe mixture is adjusted to between 3.0 and 3.6±0.1 with gradual additionof small amounts of a basic solution such as 1 N NaOH. SWFI was thenadded to the final required volume of 500 mL.

The solution was filtered through a 0.22 μm PVDF filter into acontainer. A 0.45 μm PVDF may be used to pre-filter the solution.Finally, 10.25 mL of the filtered solution was transferred into 20 mLvials (Type I boro-silicate glass vials) that had been flushed withsterile nitrogen gas prior to use. The filled vials were then stopperedusing Fluorotec B2-40 stoppers. The vials may be stored at or below 8°C. and above freezing.

Example 226

Using a procedure similar to the one in Example 225, a 7 mg/mL ±0.3solution of Example 88 may be prepared where the pH of the finalsolution is pH 2.5 to 3.0±0.1 and the final volume in each vial is 35mL. The vials may be stored at or below 8° C. and above freezing.

Example 227

A diluent for use in combination with a formulation of Examples 225 orwith other formulations containing a compound of the present inventionmay be prepared as follows.

SWFI (490 mL) that was degassed with sterile nitrogen gas wastransferred into a container and the pH was adjusted to pH 11.0 to11.4+0.1. SWFI was then added to the final required volume of 500 mL.The solution was then filtered through a 0.22 μm PVDF filter into a 0.22μm PVDF filter into a container. Finally, 10.25 mL of the filteredsolution was transferred into 20 mL vials (Type I boro-silicate glassvials) that had been flushed with sterile nitrogen gas prior to use.

Example 228

Using a procedure similar to the one in Example 227, a diluent wasprepared having a pH 11.0 to 11.4 ±0.1 and where 65 mL of filteredsolution was transferred into 100 mL vials.

Example 229

Prior to administration, the formulation in Example 225 was diluted withthe diluent in Example 227 where the contents the diluent (10.25 mL)were transferred in small amounts into the vial containing Example 225such that the final concentration of Example 88 was 1 mg/mL and thefinal pH was 5.5±0.1. The combined solution showed no precipitate andwas stabile at between 15 to 30° C. for a sufficient period to enabledose preparation and dosing. Such a period was at least 1 to 6 hours.

Example 230

Prior to administration, the formulation in Example 226 was diluted withthe diluent in Example 228 where the contents the diluent (65 mL) weretransferred in small amounts into the vial containing Example 226 suchthat the final concentration of Example 88 was 2 mg/mL and the final pHwas 4.5±0.1. The combined solution showed no precipitate and was stabileat between 15 to 30° C. for a sufficient period to enable dosepreparation and dosing. Such a period was at least 1 to 6 hours and maybe as long as 24 hours.

While the invention has been described and illustrated with reference tocertain embodiments thereof, those skilled in the art will appreciatethat various changes, modifications and substitutions can be madetherein without departing from the spirit and scope of the invention.For example, effective dosages other than the dosages as set forthherein may be applicable as a consequence of variations in theresponsiveness of the subject being treated for an Aurora kinasemediated disorder. Likewise, the specific pharmacological responsesobserved may vary according to and depending on the particular activecompound selected or whether there are present pharmaceutical carriers,as well as the type of formulation and mode of administration employed,and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvention.

1. A compound of Formula (I):

wherein X is —NH—, —O—, or —S—, E is —CH₂—, —NH—, —O—, or —S—, G¹ and G²are independently selected from the group consisting of: aryl,heteroaryl, fused arylcycloalkyl, fused cycloalkylaryl, fusedcycloalkylheteroaryl, fused heterocyclylaryl, and fusedheterocyclylheteroaryl group, wherein G¹ and G² are optionallysubstituted 1 to 7 times with substituents independently selected fromthe group consisting of R^(b); L¹ is selected from the group consistingof: a direct bond, —CH₂—, —O—, —O—CH₂—, —CH₂—O—, —N(R⁶)—, —C(O)—,—C(O)N(R⁶)—, —N(R⁶)C(O)—, —N(R⁶)C(O)N(R⁷)—, —N(R⁶)C(O)—, —OC(O)N(R⁶)—,—N(R⁶)SO₂—, —SO₂N(R⁶)—, —C(O)—O—, —O—C(O)—, —S—, —S(O)—, —S(O)₂—,—N(R⁶)SO₂N(R⁷)—, —N═N—, —C(R⁸)═C(R⁹)—, and —C≡C—, wherein R⁶ and R⁷ areindependently selected from the group consisting of R^(d) and R^(e); andR⁸ and R⁹ are independently selected from the group consisting of R^(e)and R^(f), A is a direct bond or the group -L²-Y-L³-, wherein L² and L³are independently selected from the group consisting of: a direct bond,—C₁₋₁₀ alkylene, —C₂₋₁₀ alkenylene, —C₂₋₁₀ alkynylene, -arylene,-heteroarylene, -cycloalkylene, and -heterocyclylene, wherein the carbonatoms of the alkylene, alkenylene, alkynylene, arylene, heteroarylene,cycloalkylene, and heterocyclylene groups are optionally substituted 1-4times with a substituent independently selected from R^(c); Y is adirect bond, —O—, —N(R¹⁰), —S—, SO₂—, —C(O)N(R¹⁰)—, —N(R¹⁰)—C(O)—,—N(R¹¹)C(O)N(R¹⁰)—, —N(R¹⁰)SO₂—, —SO₂N(R¹⁰)—, —C(O)—O—,—N(R¹¹)SO₂N(R¹⁰)—, —O—CO—, or —N═N—, wherein R¹⁰ and R¹¹ areindependently selected from the group consisting of: R^(d) and R^(e),and Q is selected from the group consisting of

wherein R¹⁶ and R¹⁷ are independently selected from the group consistingof: R^(d) and R^(e); 2) -heteroaryl; -heterocyclyl; -fusedcycloalkylheteroaryl; -fused heterocyclylaryl; -fusedheterocyclylheteroaryl; -fused arylheterocyclyl; -fusedheteroarylcycloalkyl; and -fused heteroarylheterocyclyl; wherein theheteroaryl, heterocyclyl, fused cycloalkylheteroaryl, fusedheterocyclylaryl, fused heterocyclylheteroaryl, fused arylheterocyclyl,fused heteroarylcycloalkyl, and fused heteroarylheterocyclyl groups areoptionally substituted 1-4 times with a substituent independentlyselected from R^(c); and 3) a ring system comprising at least onenitrogen atom selected from the group consisting of:

wherein n, m, p, q and r are independently 0-4 such that n+m+p equalsfrom 2-5 and q+r equals from 2-5, and the cycloalkyl or heterocyclo ringsystem is optionally substituted on the (CH₂) carbon atoms 1-2 with R¹⁸or R¹⁹, wherein R¹⁸ and R¹⁹ are independently selected from the groupconsisting of R^(f) and R^(g), J¹ is selected from the group consistingof:

J³ and J⁵ are independently selected from the group consisting of —CH₂—,—O—, —S—, —S(O)₂—, —C(O)—, —C(O)N(H)—, —NHC(O)—, —NHC(O)N(H)—, —NHSO₂—,—SO₂N(H)—, —C(O)—O—, —O—C(O)—, —NHSO₂NH—,

R²⁹ and R³⁰ are independently selected from the group consisting ofR^(d) and R^(e); R³¹ is R^(f); and R¹ is R^(b); R^(b) is a) -cycloalkyl,b) -cyano, c) —OR^(d), d) —NO₂, e) -halogen, f) -haloalkyl, g)—S(O)_(s)R^(d), h) —SR^(d), i) —S(O)₂OR^(d), j) —S(O)_(n)NR^(d)R^(e), k)—NR^(d)R^(e), l) —O(CR^(f)R^(g))_(t)NR^(d)R^(e), m) —C(O)R^(d), n)—CO₂R^(d), o) —CO₂(CR^(f)R^(g))_(t)C(O)NR^(d)R^(e), p) —OC(O)R^(d), q)—C(O)NR^(d)R^(e), r) —NR^(d)C(O)R^(e), s) —OC(O)NR^(d)R^(e), t)—NR^(d)C(O)OR^(e), u) —NR^(d)C(O)NR^(d)R^(e), v) —CF₃, w) —OCF₃ x)—C₁₋₁₀ alkyl, y) —C₂₋₁₀ alkenyl, z) —C₂₋₁₀ alkynyl, aa) —C₁₋₁₀alkylene-aryl, bb) —C₁₋₁₀ alkylene-heteroaryl, or cc) -heteroaryl,wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, and cycloalkyl groupsare optionally substituted 1-4 times with a substituent independentlyselected from R^(c); R^(c) is a) -halogen, b) -amino, c) -carboxy, d)—C₁₋₄ alkyl, e) —O—C₁₋₄ alkyl, f) -cycloalkyl, g) —O-cycloalkyl, h)-aryl, i) —C₁₋₄ alkylene-aryl, j) -hydroxy, k) —CF₃, l) —O-aryl, m)-heteroaryl, n) -heteroaryl-C₁₋₁₀ alkyl, o) heterocyclyl, p) —CO₂—C₁₋₁₀alkyl, or q) —CO₂—C₁₋₁₀ alkyl-aryl, R^(d) and R^(e) are independentlyselected from hydrogen, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl, aryl, heterocyclyl, whereinalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl groups areoptionally substituted with one to four substituents independentlyselected from R^(c); or R^(d) and R^(e) together with the atoms to whichthey are attached form a heterocyclic ring of 5 to 7 members containing0-2 additional heteroatoms independently selected from oxygen, sulfurand nitrogen and optionally substituted with 1-3 times with R^(c), R^(f)and R^(g) are independently selected from hydrogen, C₁₋₁₀ alkyl,cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl, and aryl, wherein alkyl,cycloalkyl, and aryl groups are optionally substituted with one to foursubstituents independently selected from R^(c); or R^(f) and R^(g)together with the carbon to which they are attached form a ring of 5 to7 members containing 0-2 heteroatoms independently selected from oxygen,sulfur and nitrogen optionally substituted with 1-3 times with R^(c), sis an integer from 1 to 2, t is an integer from 1 to 10, u is an integerfrom 0 to 1, v is an integer from 0 to 2, or a pharmaceuticallyacceptable salt or prodrug thereof.
 2. The compound of Formula (I) inclaim 1 or a pharmaceutically acceptable salt thereof, wherein X is—NH—.
 3. The compound of Formula (I) in claim 1 or a pharmaceuticallyacceptable salt thereof, wherein X is —NH— and E is —NH—.
 4. Thecompound of Formula (I) in claim 1 or a pharmaceutically acceptable saltthereof, wherein G² is selected from the group consisting of: phenyl,naphthyl, isoquinolin-3-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl,thiophen-2-yl, thiazole-2-yl, imidazole-2-yl, benzothiazole-2-yl, and4,5,6,7-tetrahydro-thiazolo[5,4-c]-pyridine-2-yl, wherein G² isoptionally substituted 1-4 times with a substituent selected from thegroup consisting of R^(b).
 5. The compound of Formula (I) in claim 1 ora pharmaceutically acceptable salt thereof, wherein G² is substitutedwith at least one substituent selected from the group consisting of:halo, phenyl, C₁₋₁₀ alkyl, piperazine-1-yl, 4-(C₁₋₁₀alkyl)-piperazine-1-yl, C₁₋₁₀ alkoxy, haloalkyl, cycloalkyl, and C₁₋₁₀alkylene-cycloalkyl.
 6. The compound of Formula (I) in claim 1 or apharmaceutically acceptable salt thereof, wherein G2 is phenyl,naphthyl, isoquinolin-3-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl,thiophen-2-yl, thiazole-2-yl, imidazole-2-yl, benzothiazole-2-yl,wherein G² is unsubstituted or substituted with at least one substituentselected from the group consisting of: chloro, fluoro, methyl, ethyl,propyl, isopropyl, tert-butyl, butyl, phenyl, methoxy, trifluoromethyl,trifluoromethoxy, and cyclopentyl.
 7. The compound of Formula (I) inclaim 1 or a pharmaceutically acceptable salt thereof, wherein L¹ is—C(O)—NH— or —NH—C(O)—.
 8. The compound of Formula (I) in claim 1 or apharmaceutically acceptable salt thereof, wherein L¹ is —C(R⁸)═C(R⁹)—.9. The compound of Formula (I) in claim 1 or a pharmaceuticallyacceptable salt thereof, wherein G¹ is selected from the groupconsisting of: phenyl, pyrazole-3-yl, benzothiazole-5-yl,benzothiazole-6-yl, benzimidazole-5-yl, benzimidazole-6-yl,benzoxazole-5-yl, benzoxazole-6-yl, benzotriazole-5-yl,benzotriazole-6-yl, benzoisoxazole-5-yl, benzoisoxazole-6-yl,indole-5-yl, indole-6-yl, 2H-indazole-6-yl, 1H-indazole-3-yl,1H-indazole-4-yl, 1H-indazole-5-yl, 1H-indazole-6-yl, quinoline-6-yl,quinoline-7-yl, quinazoline-4-yl, 2-oxindole-5-yl, 2-oxindole-6-yl,2-(1H)-benzimidazolone-5-yl, 3-indazolinone-5-yl, and3-indazolinone-6-yl, wherein G¹ is optionally substituted 1-4 times witha substituent selected from the group consisting of R^(b).
 10. Thecompound of Formula (I) in claim 1 or a pharmaceutically acceptable saltthereof, wherein G¹ is unsubstituted or substituted with at least onegroup selected from the group consisting of: halo, phenyl, C₁₋₁₀ alkyl,piperazine-1-yl, 4-(C₁₋₁₀ alkyl)-piperazine-1-yl, —C₁₋₁₀ alkoxy, —C₁₋₁₀alkylene-OH, -haloalkyl, -cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl,morpholine-4-yl, —C₁₋₁₀-alkylene-morpholine-4-yl, pyrrole-1-yl, -amino,—NH—(C₁₋₁₀ alkyl), —N(C₁₋₁₀ alkyl)₂, —NHC(O)—C₁₋₁₀ alkyl,—NHC(O)-(1-(C₁₋₁₀ alkyl)-piperidine-4-yl), —NH C(O)-phenyl, —NH—C₁₋₁₀alkylene-morpholine-4-yl, —O—C₁₋₁₀ alkylene-morpholine-4-yl, and—NH—C₁₋₁₀ alkylene-OH.
 11. The compound of Formula (I) in claim 1 or apharmaceutically acceptable salt thereof, wherein L¹ is —NHC(O)— or—C(O)—NH—, and G¹ is 1H-indazole-5-yl or 1H-indazole-6-yl, wherein G¹ isoptionally substituted 1-4 times with a substituent selected from thegroup consisting of R^(b).
 12. The compound of Formula (I) in claim 1 ora pharmaceutically acceptable salt thereof, wherein G¹ is1H-indazole-5-yl or 1H-indazole-6-yl, wherein G¹ is unsubstituted orsubstituted at the 3-position with a substituent selected from the groupconsisting of: halo, phenyl, C₁₋₁₀ alkyl, piperazine-1-yl, 4-(C₁₋₁₀alkyl)-piperazine-1-yl, —C₁₋₁₀ alkoxy, —C₁₋₁₀ alkylene-OH, -haloalkyl,-cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl, morpholine-4-yl,—C₁₋₁₀-alkylene-morpholine-4-yl, pyrrole-1-yl, -amino, —NH—(C₁₋₁₀alkyl), —N(C₁₋₁₀ alkyl)₂, —NHC(O)—C₁₋₁₀ alkyl, —NHC(O)-(1-(C₁₋₁₀alkyl)-piperidine-4-yl), —NHC(O)-phenyl, —NH—C₁₋₁₀alkylene-morpholine-4-yl, —O—C₁₋₁₀ alkylene-morpholine-4-yl, and—NH—C₁₋₁₀ alkylene-OH.
 13. The compound of Formula (I) in claim 1 or apharmaceutically acceptable salt thereof, wherein u is 1, A is a directbond, and Q is selected from the group consisting of: 4-(C₁₋₁₀alkyl)-piperazine-1-yl, piperadine-1-yl, morpholine-4-yl, —NH—C₁₋₁₀alkyl, —N—(C₁₋₁₀ alkyl)₂, —N—(C₁₋₁₀ alkyl)(cycloalkyl), and—NH-cycloalkyl.
 14. The compound of Formula (I) in claim 1 or apharmaceutically acceptable salt thereof, wherein u is zero and v iszero.
 15. The compound of Formula (I) in claim 1 or a pharmaceuticallyacceptable salt thereof, wherein u is 1 and v is zero.
 16. The compoundof Formula (I) in claim 1 or a pharmaceutically acceptable salt thereof,wherein u is zero and v is one.
 17. The compound of Formula (I) in claim1 or a pharmaceutically acceptable salt thereof, wherein u is zero, v isone, and R¹ is selected from the group consisting of: —C₁₋₁₀ alkyl,-cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl, —C₁₋₁₀ haloalkyl, -phenyl,—O—C₁₋₁₀ alkyl, —O-cycloalkyl, and —O—C₁₋₁₀ haloalkyl.
 18. The compoundof Formula (I) in claim 1 or a pharmaceutically acceptable salt thereof,wherein X is —NH—, E is —NH—, v is zero, L¹ is —NHC(O)— or —C(O)NH—, G¹is 1H-indazol-6-yl or 1H-indazol-5-yl, wherein G¹ is optionallysubstituted 1-4 times with a substituent selected from the groupconsisting of R^(b).
 19. The compound of Formula (I) in claim 18 or apharmaceutically acceptable salt thereof, wherein G¹ is unsubstituted.20. The compound of Formula (I) in claim 1 having the formula:

wherein G¹, G², L¹, Q, and A are as defined in claim
 1. 21. The compoundof Formula (I) in claim 1 or a pharmaceutically acceptable salt thereofhaving the formula:

wherein G¹, G², and Q are as defined in claim
 1. 22. The compound ofFormula (Ib) in claim 21 or a pharmaceutically acceptable salt thereof,wherein Q is selected from the group consisting of: 4-(C₁₋₁₀alkyl)-piperazine-1-yl, piperadine-1-yl, morpholine-4-yl, —NH—C1-oalkyl, —N—(C₁₋₁₀ alkyl)₂, —N—(C₁₋₁₀ alkyl)(cycloalkyl), and—NH-cycloalkyl.
 23. The compound of Formula (Ib) in claim 21 or apharmaceutically acceptable salt thereof, wherein G² is selected fromthe group consisting of: phenyl, naphthyl, isoquinolin-3-yl,pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, thiophen-2-yl,thiazole-2-yl, imidazole-2-yl, benzothiazole-2-yl, and4,5,6,7-tetrahydro-thiazolo[5,4-c]-pyridine-2-yl, wherein G² isoptionally substituted 1-4 times with a substituent selected from thegroup consisting of R^(b).
 24. The compound of Formula (Ib) in claim 21or a pharmaceutically acceptable salt thereof, wherein G¹ is selectedfrom the group consisting of: phenyl, pyrazole-3-yl, benzothiazole-5-yl,benzothiazole-6-yl, benzimidazole-5-yl, benzimidazole-6-yl,benzoxazole-5-yl, benzoxazole-6-yl, benzotriazole-5-yl,benzotriazole-6-yl, benzoisoxazole-5-yl, benzoisoxazole-6-yl,indole-5-yl, indole-6-yl, 2H-indazole-6-yl, 1H-indazole-3-yl,1H-indazole-4-yl, 1H-indazole-5-yl, 1H-indazole-6-yl, quinoline-6-yl,quinoline-7-yl, quinazoline-4-yl, 2-oxindole-5-yl, 2-oxindole-6-yl,2-(1H)-benzimidazolone-5-yl, 3-indazolinone-5-yl, and3-indazolinone-6-yl, wherein G¹ is optionally substituted 1-4 times witha substituent selected from the group consisting of R^(b).
 25. Thecompound of Formula (Ib) in claim 21 or a pharmaceutically acceptablesalt thereof, wherein G¹ is 1H-indazol-6-yl or 1H-indazol-5-yl, whereinG¹ is optionally substituted 1-4 times with a substituent selected fromthe group consisting of R^(b).
 26. The compound of Formula (I) in claim1 or a pharmaceutically acceptable salt thereof having the formula:

wherein G¹, G², and R¹ are as defined in clam
 1. 27. The compound ofFormula (Ic) in claim 26 or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from the group consisting of: —C₁₋₁₀ alkyl,-cycloalkyl, —C₁₋₁₀ alkylene-cycloalkyl, —C₁₋₁₀ haloalkyl, -phenyl,—O—C₁₋₁₀ alkyl, —O-cycloalkyl, and —O—C₁₋₁₀ haloalkyl.
 28. The compoundof Formula (Ic) in claim 26 or a pharmaceutically acceptable saltthereof, wherein G² is selected from the group consisting of: phenyl,naphthyl, isoquinolin-3-yl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl,thiophen-2-yl, thiazole-2-yl, imidazole-2-yl, benzothiazole-2-yl, and4,5,6,7-tetrahydro-thiazolo[5,4-c]-pyridine-2-yl, wherein G² isoptionally substituted 1-4 times with a substituent selected from thegroup consisting of R^(b).
 29. The compound of Formula (Ic) in claim 26or a pharmaceutically acceptable salt thereof, wherein G¹ is selectedfrom the group consisting of: phenyl, pyrazole-3-yl, benzothiazole-5-yl,benzothiazole-6-yl, benzimidazole-5-yl, benzimidazole-6-yl,benzoxazole-5-yl, benzoxazole-6-yl, benzotriazole-5-yl,benzotriazole-6-yl, benzoisoxazole-5-yl, benzoisoxazole-6-yl,indole-5-yl, indole-6-yl, 2H-indazole-6-yl, 1H-indazole-3-yl,1H-indazole-4-yl, 1H-indazole-5-yl, 1H-indazole-6-yl, quinoline-6-yl,quinoline-7-yl, quinazoline-4-yl, 2-oxindole-5-yl, 2-oxindole-6-yl,2-(1H)-benzimidazolone-5-yl, 3-indazolinone-5-yl, and3-indazolinone-6-yl, wherein G¹ is optionally substituted 1-4 times witha substituent selected from the group consisting of R^(b).
 30. Thecompound of Formula (Ic) in claim 26 or a pharmaceutically acceptablesalt thereof, wherein G¹ is 1H-indazol-6-yl or 1H-indazol-5-yl, whereinG¹ is optionally substituted 1-4 times with a substituent selected fromthe group consisting of R^(b).
 31. The compound of Formula (I) in claim1 selected from the group consisting of:4-[6-(1H-Indazol-6-ylcarbamoyl)-2-(2-trifluoromethylphenylamino)-3H-benzimidazol-5-yl]-piperazine-1-carboxylicacid tert-butyl ester,6-piperazin-1-yl-2-(2-trifluoromethylphenylamino)-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide,4-[6-(1H-Indazol-6-ylcarbamoyl)-2-(3-methylpyridin-2-ylamino)-3H-benzimidazol-5-yl]-piperazine-1-carboxylicacid tert-butyl ester,2-(3-Methylpyridin-2-ylamino)-6-piperazin-1-yl-1H-benzimidazole-5-carboxylicacid (1H-indazol-6-yl)-amide, or a pharmaceutically acceptable saltthereof.
 32. A pharmaceutical composition comprising a compound ofFormula (I) in claim 1 or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.
 33. The pharmaceuticalcomposition of claim 32 comprising a therapeutically effective amount ofthe compound of Formula (I) or a pharmaceutically acceptable saltthereof.
 34. The pharmaceutical composition of claim 32 furthercomprising an additional therapeutic agent selected from the groupconsisting of antimetabolites, protein tyrosine kinase inhibitors, andantibodies.
 35. A method for inhibiting Aurora kinase activitycomprising contacting a cell in a subject in which inhibition of Aurorakinase A or B is desired with a compound of Formula (I) in claim 1 or apharmaceutically acceptable salt thereof.
 36. A method for treating anAurora kinase-mediated disorder in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I) in claim 1 or a pharmaceutically acceptable saltthereof.
 37. The method according to claim 36, wherein the Aurorakinase-mediated disorder is a cancer.
 38. The method according to claim37, wherein the cancer is selected from the group consisting ofcolorectal cancer, ovarian cancer, breast cancer, gastric cancer,prostate cancer, brain cancer, bone cancer, bladder cancer, head andneck cancer, lung cancer, renal cancer, pancreatic cancer, sarcoma,leukemia, and lymphoma.
 39. The method according to claim 38, whereinthe cancer is selected from the group consisting of breast cancer,colorectal cancer, and pancreatic cancer.
 40. The method of claim 36,further comprising the step of administering to a subject an additionaltherapeutic agent selected from the group consisting of:antimetabolites, protein tyrosine kinase inhibitors, and antibodies.